Ointment containing an oxazole compound

ABSTRACT

An ointment is provided. The ointment stably comprises an oxazole compound that has specific inhibitory activity against PDE4 and that is represented by the following formula (11). The ointment can be efficiently absorbed into the skin.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/782,259 filed Feb. 5, 2020, which is a continuation of U.S.application Ser. No. 16/064,618 filed Jun. 21, 2018, now U.S. Pat. No.10,588,893, which is a National Stage of International Application No.PCT/JP2016/088843 filed Dec. 27, 2016, claiming priority based onJapanese Patent Application No. 2015-256784 filed Dec. 28, 2015. Theentire disclosures of the prior applications are incorporated herein byreference.

TECHNICAL FIELD

The present invention relates to an ointment comprising an oxazolecompound.

BACKGROUND ART

PTL 1 and 2 report an oxazole compound having specific inhibitoryactivity against phosphodiesterase 4 (PDE4) and a method for producingthe oxazole compound. PDE4 is predominant in inflammatory cells.Inhibition of PDE4 increases intracellular cAMP levels, and increasedcAMP levels down-regulate inflammatory response through expressionregulation of TNF-α, IL-23, or other inflammatory cytokines. Increasesin cAMP levels also increase anti-inflammatory cytokines, such as IL-10.Thus, the oxazole compound is thought to be suitable for use as ananti-inflammatory agent. For example, the oxazole compound is thought tobe useful to reduce or eliminate eczema or dermatitis, including atopicdermatitis.

However, so far there has been no ointment that stably contains anoxazole compound having specific inhibitory activity against PDE4 andthat can be efficiently absorbed into the skin.

CITATION LIST Patent Literature

[PTL 1] WO2007/058338 Pamphlet (JP2009-515872A)

[PTL 2] WO2014/034958 Pamphlet (JP2015-528433A)

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide an ointment that stablycomprises an oxazole compound having specific inhibitory activityagainst PDE4 and that can be efficiently absorbed into the skin.

Solution to Problem

The present inventors found that dissolving a specific oxazole compound,among oxazole compounds having specific inhibitory activity againstPDE4, in a specific solvent and dissolving or dispersing the resultingsolution in a base material can provide an ointment that stably containsthe specific oxazole compound and that can be efficiently absorbed intothe skin. The inventors further made modification and completed thepresent invention.

Specifically, the present invention encompasses, for example, thefollowing subject matters.

Item 1. An ointment comprising an oxazole compound represented by thefollowing formula (11):

Item 2. The ointment according to Item 1, comprising the oxazolecompound dissolved in a base component.Item 3. The ointment according to Item 2, wherein the base componentcomprises a solvent for dissolving the oxazole compound in the solvent,and an ointment base for dispersing or dissolving the solvent in theointment base.Item 4. The ointment according to Item 3, wherein the ointment basecomprises a hydrocarbon (preferably, at least one hydrocarbon selectedfrom the group consisting of petrolatum, paraffin, wax, and beeswax).Item 5. The ointment according to Item 3 or 4, wherein the solventcomprises a polar compound that is a liquid at room temperature(preferably, at least one member selected from the group consisting ofethylene carbonate, propylene carbonate, benzyl alcohol, triacetin,N-methylpyrrolidone, diethyl sebacate, diisopropyl sebacate, diethyladipate, diisopropyl adipate, isostearyl alcohol, and isopropylmyristate).Item 6. The ointment according to any one of Items 3 to 5, wherein theointment base is an ointment base for dispersing the solvent in theointment base, and the solvent in the form of droplets, in which theoxazole compound is dissolved, is dispersed in the ointment base.Item 7. The ointment according to any one of Items 3 to 6, wherein theointment base comprises at least beeswax.Item 8. The ointment according to Item 7, wherein the beeswax is notchemically bleached.Item 9. The ointment according to any one of Items 1 to 8, for use inthe treatment and/or prevention of eczema and dermatitis (preferablyatopic dermatitis).Item 10. An ointment comprising:

-   -   (I) an oxazole compound represented by formula (11),    -   (II) a solvent comprising at least one member selected from the        group consisting of ethylene carbonate, propylene carbonate,        benzyl alcohol, and triacetin, and    -   (III) beeswax,        wherein component (II) in the form of droplets, in which        component (I) is dissolved, is dispersed in component (III), and        the droplets have a mean particle size of 100 μm or less.        Item A. A method for producing a compound represented by formula        (3)

wherein X¹ represents halogen, and R¹ represents an alkali metal orlower alkyl, the method comprising:

-   -   (a) reacting a compound represented by formula (1a) with a        compound represented by formula X¹CF₂COOR¹ to produce a compound        represented by formula (2); and    -   (b) oxidizing the compound represented by formula (2) to produce        a compound represented by formula (3).        Item B. A method for producing a compound represented by formula        (3)

wherein X² represents halogen, the method comprising:

-   -   (a) reacting a compound represented by formula (1b) with a        compound represented by formula X²CH(CH₃)₂ to produce a compound        represented by formula (2), and    -   (b) oxidizing the compound represented by formula (2) to produce        a compound represented by formula (3).

Advantageous Effects of Invention

The ointment according to the present invention stably contains anoxazole compound having specific inhibitory activity against PDE4, andthe ointment can be efficiently absorbed into the skin.

DESCRIPTION OF EMBODIMENTS

The ointment according to the present invention comprises a specificoxazole compound, which is preferably dissolved in a base component. Theoxazole compound can be contained in an ointment as an active component.The base component as used here encompasses a solvent for dissolving theoxazole compound in the solvent, and one or more other ointment bases.The ointment base is preferably an ointment base in which the solventcan be dispersed or dissolved.

In other words, the ointment according to the present inventioncomprises (I) a specific oxazole compound, which is preferably dissolvedin a base component, and the base component includes (II) a solvent fordissolving the oxazole compound in the solvent and (III) an ointmentbase.

More preferably, the ointment according to the present invention is anointment wherein component (II) in the form of droplets, in whichcomponent (I) is dissolved, is dissolved or dispersed in component(III).

Examples of oxazole compound (I) include compounds represented by thefollowing formulae (11) and (11a) to (11s). In particular, the compoundrepresented by formula (11) is preferable.

TABLE 1 Formula Number Structural Formula 11a

11b

11c

11d

11e

11f

11g

11h

11i

11j

11k

11l

11m

11n

11o

11p

11q

11r

11s

These oxazole compounds can be used singly or in a combination of two ormore. Specifically, the ointment of the present invention comprises atleast one oxazole compound selected from the group consisting ofcompounds represented by formulae (11) and (11a) to (11s).

Although there is no particular limitation, oxazole compound (I) ispresent in the ointment in an amount of preferably 0.01 to 10 parts byweight, more preferably 0.05 to 7.5 parts by weight, still morepreferably 0.1 to 5 parts by weight, per 100 parts by weight of theointment.

As stated above, the oxazole compound is preferably dissolved in solvent(II). The solvent is preferably a polar compound that is a liquid atroom temperature. Specific examples of the solvent include ethylenecarbonate, propylene carbonate, benzyl alcohol, triacetin, diethylsebacate, diisopropyl sebacate, diethyl adipate, diisopropyl adipate,isostearic acid, olive oil, hexyldodecanol, decyl oleate, isostearylalcohol, and isopropyl myristate. Ethylene carbonate, propylenecarbonate, benzyl alcohol, and triacetin are more preferable, andpropylene carbonate and triacetin are still more preferable. Of these,propylene carbonate is preferable. These solvents can be used singly orin a combination of two or more. In particular, it is preferable to useethylene carbonate or propylene carbonate alone, or a combination ofethylene carbonate or propylene carbonate with benzyl alcohol and/ortriacetin.

Solvent (II) is present in the ointment in an amount of preferably morethan 2 parts by weight, more preferably 2.1 parts by weight or more, andstill more preferably 2.2 parts by weight or more, per part by weight ofoxazole compound (I). The upper limit of the amount of solvent (II) isnot particularly limited, as long as the effect of the present inventionis produced. For example, the upper limit is preferably 30 parts byweight or less, more preferably 20 parts by weight or less, and stillmore preferably 15 parts by weight or less.

Solvent (II) is present in the ointment in an amount of preferably 0.1to 50 parts by weight, more preferably 0.2 to 25 parts by weight, andstill more preferably 0.5 to 20 parts by weight, per 100 parts by weightof the ointment.

A solution of the oxazole compound in the solvent is preferablydissolved or dispersed in the form of droplets in ointment base (III),and more preferably dispersed in the form of droplets in ointment base(III).

Known ointment bases for use in the production of ointments can be usedas ointment base (III). Examples of ointment bases include hydrocarbons,and more specific examples include grease bases, particularly naturalwax, petroleum wax, and other hydrocarbons. Examples of natural waxinclude beeswax (e.g., unbleached beeswax, non-chemically bleachedbeeswax, and chemically bleached beeswax), and carnauba wax. Examples ofpetroleum wax include paraffin and microcrystalline wax. Examples ofother hydrocarbons include liquid paraffin and petrolatum (e.g., whitepetrolatum and yellow petrolatum). These ointment bases can be usedsingly or in a combination of two or more.

Ointment base (III) is present in the ointment in an amount ofpreferably 5 to 5000 parts by weight, more preferably 10 to 2500 partsby weight, and still more preferably 20 to 1000 parts by weight, perpart by weight of oxazole compound (I).

Ointment base (III) is present in the ointment in an amount ofpreferably 50 to 99 parts by weight, more preferably 70 to 98 parts byweight, and still more preferably 80 to 97 parts by weight, per 100parts by weight of the ointment.

Ointment base (III) preferably comprises at least beeswax. The beeswaxfor use is preferably beeswax that is not chemically bleached,including, for example, beeswax that is non-chemically bleached(non-chemically bleached beeswax) and beeswax that is not bleached(unbleached beeswax).

The beeswax is present in the ointment in an amount of preferably 0.05to 50 parts by weight, more preferably 0.1 to 40 parts by weight, andstill more preferably 0.2 to 35 parts by weight, per part by weight ofoxazole compound (I).

The beeswax is present in the ointment in an amount of preferably 0.1 to10 parts by weight, more preferably 0.2 to 9 parts by weight, still morepreferably 0.4 to 8 parts by weight, even still more preferably 0.5 to7.5 parts by weight, and particularly preferably 1 to 5 parts by weight,per 100 parts by weight of the ointment.

When other ointment bases are combined with beeswax, the combination isnot particularly limited. However, for example, the combinationpreferably comprises at least one member selected from the groupconsisting of petrolatum (preferably white petrolatum), liquid paraffin,and paraffin and beeswax.

In addition to the ointment base, the ointment may comprise otheradditives for use in ointments (in particular, pharmaceuticaladditives), such as aroma components, colorants, preservatives,absorption promoters including higher alkene acids (e.g., oleic acid),or medicaments effective for treating other skin diseases.

As stated above, the ointment of the present invention is preferably anointment wherein solvent (II), in which oxazole compound (I) isdissolved, is dissolved or dispersed in the form of droplets in ointmentbase (III). Examples of the method for producing this ointment include amethod comprising preparing a solution of component (I) in component(II), and mixing the solution with component (III) with stirring. Mixingwith stirring can be performed with, for example, a homomixer, a paddlemixer, or a combination of these mixers.

In the use of multiple types of ointment bases (component (III)), it ispreferable to mix the multiple ointment bases beforehand. In theformulation of component (III) containing multiple types of ointmentbases, it is preferable to mix the ointment bases with heating to meltthe solids, such as beeswax. For example, when beeswax and otherointment bases are used in combination, beeswax and other ointment basesare preferably mixed beforehand, preferably with heating.

In the case of an ointment wherein component (II), in which component(I) is dissolved, is dispersed in the form of droplets in component(III), the particle size of the droplets observed with a polarizingmicroscope is 100 μm or less, preferably about 40 μm or less, morepreferably about 25 μm or less, and still more preferably about 20 μm orless. In particular, there exist preferably no droplets having aparticle size of more than 100 μm, more preferably no droplets having aparticle size of more than 40 μm, still more preferably no dropletshaving a particle size of more than 25 μm, and even still morepreferably no droplets having a particle size of more than 20 μm. Adesired mean particle size of the droplets is achieved by adjusting thestirring rate at which the solution is mixed with component (III) withstirring.

The oxazole compound represented by formula (11) is a known compounddisclosed in PTL 1 and 2, and can be produced in accordance with theprocedure described in PTL 1 or 2.

The oxazole compound represented by formula (11) can also be produced asdescribed below. The compounds used as starting materials below areknown or easily produced from known compounds.

Specifically, compound (3) is first synthesized, and then compound (7)is synthesized from compound (3). Subsequently, compound (11) issynthesized from compound (7). In this specification, a compoundrepresented by formula A may be indicated as compound A or compound (A).

Production of Compound (3)

Compound (3) can be produced, for example, through the reaction stepsillustrated in the following reaction scheme.

Compound (1a)+Compound X¹CF₂COOR¹→Compound (2)

Compound (2) can be produced by reacting compound (1a) with compoundX¹CF₂COOR¹ in the presence of a base.

In compound X¹CF₂COOR¹, X¹ represents halogen, and the halogen includesfluorine, chlorine, bromine, and iodine, with chlorine, bromine, andiodine being preferable, and chlorine being more preferable.

R¹ represents an alkali metal or lower alkyl. The alkali metal includeslithium, sodium, and potassium, with sodium being preferable. The loweralkyl includes C1-C6 (in particular, C1-C4) linear or branched alkyl.Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, 1-ethyl propyl, n-pentyl, neopentyl,n-hexyl, isohexyl, and 3-methyl pentyl, with methyl and ethyl beingpreferable.

The reaction can be performed in the presence of a common solvent. Thesolvent can be any solvent that does not adversely affect the reaction.Examples of the solvent include ketone solvents (e.g., acetone andmethyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane,diethyl ether, and diglyme), ester solvents (e.g., methyl acetate andethyl acetate), aprotic polar solvents (e.g., acetonitrile,N,N-dimethylformamide, and dimethyl sulfoxide), halogenated hydrocarbonsolvents (e.g., methylene chloride and ethylene chloride), andcombinations of these solvents. The solvent is preferablyN,N-dimethylformamide.

The base for use can be known inorganic bases or organic bases. Examplesof inorganic bases include alkali metals (e.g., sodium and potassium),alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate,sodium hydrogen carbonate, and potassium hydrogen carbonate), alkalimetal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassiumhydroxide, and cesium hydroxide), alkali metal carbonates (e.g., lithiumcarbonate, sodium carbonate, potassium carbonate, and cesium carbonate),alkali metal lower (C1-C3) alkoxides (e.g., sodium methoxide and sodiumethoxide), and alkali metal hydrides (e.g., sodium hydride and potassiumhydride). Examples of organic bases include trialkyl amines (e.g.,trimethylamine, triethylamine, and N,N-diisopropylethylamine), pyridine,quinoline, piperidine, imidazole, picoline, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane(DABCO), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). When these basesare a liquid, these bases can also be used as a solvent. These bases areused singly or in a combination of two or more. The base is preferablyan alkali metal carbonate (in particular, sodium carbonate or potassiumcarbonate).

The amount of the base for use is typically 1 to 10 moles, andpreferably 1 to 6 moles, per mole of compound (1a).

The reaction can be performed by optionally adding an alkali metaliodide, such as potassium iodide or sodium iodide, as a reactionaccelerator to the reaction system.

When a reaction accelerator is used, the amount of the reactionaccelerator is typically at least 0.01 moles, and preferably about 0.1to 2 moles, per mole of X¹CF₂COOR¹.

The proportion of compound (1a) and compound X¹CF₂COOR¹ is typically atleast 1 mole, preferably about 1 to 5 moles of compound X¹CF₂COOR¹, permole of compound (1a).

The reaction temperature is not particularly limited, and the reactioncan be typically performed under any of the following conditions: withcooling, at room temperature, or with heating. The reaction ispreferably performed at a temperature of about 80 to 120° C. for 1 to 30hours.

Compound (2)→Compound (3)

Compound (3) can be produced by oxidizing compound (2). Specifically,for example, compound (3) is produced by subjecting compound (2) toreaction in a solvent in the presence of an oxidant.

When compound (2) is reacted in a solvent in the presence of an oxidant,examples of the solvent for use include water; alcohols, such asmethanol, ethanol, propanol, isopropyl alcohol, n-butanol, tert-butanol,and ethylene glycol; halogenated hydrocarbons, such as dichloromethane,chloroform, and carbon tetrachloride; ethers, such as diethyl ether,tetrahydrofuran, dioxane, monoglyme, and diglyme; ketones, such asacetone and methyl ethyl ketone; aromatic hydrocarbons, such as benzene,o-dichlorobenzene, toluene, and xylene; esters, such as methyl acetate,ethyl acetate, and butyl acetate; aprotic polar solvents, such asacetonitrile, N,N-dimethylformamide, and hexamethylphosphoric triamide;and combinations of these solvents.

Oxidants include halous acids, such as chlorous acid, iodous acid, andbromous acid; alkali metal salts of halous acids, such as sodiumchlorite, sodium iodite, sodium bromite, potassium chlorite, potassiumiodite, and potassium bromite; alkali metal salts of permanganic acid,such as potassium permanganate; chromic acid or alkali metal saltsthereof, such as chromium oxide (VI), sodium dichromate, and potassiumdichromate; and nitric acid. When using an alkali metal salt ofpermanganic acid, it is preferable to perform reaction in the presenceof an inorganic base, such as potassium hydroxide, sodium hydroxide,sodium carbonate, or potassium carbonate. When using chromic acid or analkali metal salt thereof, it is preferable to perform reaction in thepresence of a mineral acid such as sulfuric acid, or an organic acidsuch as acetic acid. Of these, in particular, halous acids, and alkalimetal salts of halous acids are particularly preferable.

The amount of the oxidant for use is typically 0.5 to 1 mole or more,and preferably 1 to 10 moles, per mole of compound (2).

The reaction temperature is typically about −20 to 50° C., andpreferably about −20° C. to room temperature (25° C.). The reaction timeis about 1 to 30 hours.

Compound (3) can be produced through the reaction steps illustrated inthe following reaction scheme.

Compound (1b)+Compound X²CH(CH₃)₂→Compound (2)

Compound (2) can also be produced by reacting compound (1a) withcompound X²CH(CH₃)₂ in the presence of a base.

In compound X²CH(CH₃)₂, X² represents halogen, and the halogen includesfluorine, chlorine, bromine, and iodine, with chlorine, bromine, andiodine being preferable, and bromine being more preferable.

The reaction can be performed in the presence of a common solvent. Thesolvent can be any solvent that does not adversely effect the reaction.Examples of the solvent include ketone solvents (e.g., acetone andmethyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane,diethyl ether, and diglyme), ester solvents (e.g., methyl acetate andethyl acetate), aprotic polar solvents (e.g., acetonitrile,N,N-dimethylformamide, and dimethyl sulfoxide), halogenated hydrocarbonsolvents (e.g., methylene chloride and ethylene chloride), andcombinations of these solvents. The solvent is preferablyN,N-dimethylformamide.

The base for use can be known inorganic bases or organic bases. Examplesof inorganic bases include alkali metals (e.g., sodium and potassium),alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate,sodium hydrogen carbonate, and potassium hydrogen carbonate), alkalimetal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassiumhydroxide, and cesium hydroxide), alkali metal carbonates (e.g., lithiumcarbonate, sodium carbonate, potassium carbonate, and cesium carbonate),alkali metal lower (C1-C3) alkoxides (e.g., sodium methoxide and sodiumethoxide), and alkali metal hydrides (e.g., sodium hydride and potassiumhydride). Organic bases include trialkyl amines (e.g., trimethylamine,triethylamine, and N,N-diisopropylethylamine), pyridine, quinoline,piperidine, imidazole, picoline, 4-dimethylaminopyridine,N,N-dimethylaniline, N-methylmorpholine,1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane(DABCO), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). When these basesare a liquid, these bases can also be used as a solvent. These bases areused singly or in a combination of two or more. The base is preferablyan alkali metal carbonate (in particular, sodium carbonate or potassiumcarbonate).

The amount of the base for use is typically 1 to 10 moles, andpreferably 1 to 6 moles, per mole of compound (1b).

The reaction can be performed by optionally adding an alkali metaliodide, such as potassium iodide or sodium iodide, as a reactionaccelerator to the reaction system.

When a reaction accelerator is used, the amount of the reactionaccelerator is typically at least 0.01 moles, and preferably about 0.1to 2 moles, per mole of X²CH(CH₃)₂.

The proportion of compound (1b) and compound X²CH(CH₃)₂ for use may betypically at least 1 mole, and preferably about 1 to 5 moles of compoundX²CH(CH₃)₂, per mole of compound (1b).

The reaction temperature is not particularly limited, and the reactioncan be typically performed under any of the following conditions: withcooling, at room temperature, or with heating. The reaction ispreferably performed at a temperature within the range of around roomtemperature to about 85° C. for 1 to 30 hours.

The method for producing compound (3) from compound (2) is as describedabove.

Production of Compound (7)

Compound (7) can be produced, for example, through the reaction stepsillustrated in the following reaction scheme.

Compound (3)→Compound (4)

Compound (4) can be produced by subjecting compound (3) to condensationreaction with ammonia (amidation reaction). The reaction can betypically performed by reacting compound (3) with ammonia in a solventin the presence of a condensation agent.

The solvent can be any solvent that does not adversely effect thereaction. Examples of the solvent include halogenated aliphatichydrocarbon solvents (e.g., methylene chloride, chloroform, and ethylenechloride), ketone solvents (e.g., acetone and methyl ethyl ketone),ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether,dimethoxyethane, and diglyme), aromatic hydrocarbons (e.g., toluene andxylene), aprotic polar solvents (e.g., acetonitrile,N,N-dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide), andcombinations of these solvents. The solvent is preferably acetonitrile.

Examples of the condensation agent include 1,1′-carbonyl diimidazole(CDI), dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC orWSC), diphenylphosphoryl azide (DPPA),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium salts (e.g.,benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate), and 2-chloro-4,6-dimethoxytriazine (CDMT). Thecondensation agent is preferably CDI.

The amount of the condensation agent for use is typically at least 1mole, and preferably about 1 to 5 moles, per mole of compound (3).

Together with the condensation agent, an additive (activator), such as1-hydroxy benzotriazole (HOBt) and N-hydroxy succinimide (HOSu), mayoptionally be used.

When the additive is used, the amount of the additive is typically atleast 1 mole, and preferably about 1 to 5 moles, per mole of thecondensation agent.

The reaction can also be performed by optionally adding a base. Examplesof the base include tertiary amines, such as triethylamine andN,N-diisopropylethylamine; and nitrogen-containing aromatic compounds,such as pyridine and 4-dimethylaminopyridine.

When a base is used, the amount of the base is typically at least 1mole, and preferably about 1 to 5 moles, per mole of compound (5).

Ammonia is typically used as ammonia water. The amount of ammonia foruse is typically at least 1 mole, and preferably about 1 to 10 moles,per mole of compound (3).

The reaction is typically performed by reacting compound (3) with acondensation agent, optionally with an additive, to prepare an activatedester, and reacting the activated ester with ammonia.

The reaction temperature for the preparation of the activated ester andsubsequent reaction with ammonia is not particularly limited. Thepreparation and the reaction can be typically performed under any of thefollowing conditions: with cooling, at room temperature, or withheating. The reaction is preferably performed at a temperature withinthe range of ice cooling temperature to about room temperature for 1 to30 hours.

Compound (4)→Compound (5)

Compound (5) can be produced by reacting compound (4) with compoundCO(CH₂X³)₂.

In compound CO(CH₂X³)₂, X³ represents halogen. The halogen representedby X³ includes fluorine, chlorine, bromine, and iodine, with chlorine,bromine, and iodine being preferable.

The reaction can be performed in the presence of a common solvent. Thesolvent can be any solvent that does not adversely effect the reaction.Examples of the solvent include halogenated aliphatic hydrocarbonsolvents (e.g., methylene chloride, chloroform, and ethylene chloride),ketone solvents (e.g., acetone and methyl ethyl ketone), ether solvents(e.g., tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, anddiglyme), aromatic hydrocarbons (e.g., toluene and xylene), aproticpolar solvents (e.g., acetonitrile, N,N-dimethylformamide,N-methylpyrrolidone, and dimethyl sulfoxide), and combinations of thesesolvents. The solvent is preferably an aromatic hydrocarbon (e.g.,toluene and xylene).

The proportion of compound (4) and compound CO(CH₂X³)₂ for use istypically at least 1 mole, preferably about 1 to 5 moles of compoundCO(CH₂X³)₂, per mole of compound (4).

Optionally, a dehydrating agent may be used. Examples of the dehydratingagent include synthetic zeolite, which specifically includes molecularsieves (MS)3A, MS4A, and other similar zeolite with fine pores.

The reaction temperature is not particularly limited, and the reactioncan be typically performed under any of the following conditions: withcooling, at room temperature, or with heating. The reaction ispreferably performed at a temperature within the range of around roomtemperature to about 200° C. for 1 to 30 hours. The use of this methodenables the oxazole ring to foam at a high yield.

Compound (5)→Compound (6)

Compound (6) can be produced by reacting compound (5) with compoundR²OM¹. In compound R²OM¹, R² represents alkanoyl, and M¹ represents analkali metal.

The alkanoyl represented by R² includes C1-C6 (in particular, C1-C4)linear or branched alkanoyl. Specific examples of the alkanoyl includeformyl, acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl,sec-butyryl, tert-butyryl, and hexanoyl, with formyl, acetyl,n-propionyl, and isopropionyl being preferable, and acetyl being morepreferable.

The alkali metal represented by M¹ includes lithium, sodium, andpotassium, with sodium and potassium being preferable.

Specific examples of compound R²OM¹ include sodium acetate and potassiumacetate.

The reaction can be performed in the presence of a common solvent. Thesolvent can be any solvent that does not adversely affect the reaction.Examples of the solvent include ketone solvents (e.g., acetone andmethyl ethyl ketone), ether solvents (e.g., tetrahydrofuran, dioxane,diethyl ether, and diglyme), ester solvents (e.g., methyl acetate andethyl acetate), aprotic polar solvents (e.g., acetonitrile,N,N-dimethylformamide, and dimethyl sulfoxide), halogenated hydrocarbonsolvents (e.g., methylene chloride and ethylene chloride), andcombinations of these solvents. The solvent is preferablyN,N-dimethylformamide.

The proportion of compound (5) and compound R²OM¹ for use is typicallyat least 1 mole, and preferably about 1 to 5 moles of compound R²OM¹,per mole of compound (5).

The reaction temperature is not particularly limited, and the reactioncan be typically performed under any of the following conditions: withcooling, at room temperature, or with heating. The reaction may bepreferably performed at a temperature within the range of around roomtemperature to about 120° C. for 1 to 30 hours.

Compound (6)→Compound (7)

Compound (7) can be produced by hydrolyzing compound (6). The hydrolysisof compound (6) can be typically performed in a solvent in the presenceof a base.

The solvent can be any solvent that does not adversely affect thereaction. Examples of the solvent include water, alcohol solvents (e.g.,methanol, ethanol, isopropanol, and n-butanol), ketone solvents (e.g.,acetone and methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran,dioxane, diethyl ether, dimethoxyethane, and diglyme), and acetonitrile.Preferable examples of the solvent include a combination solvent ofwater and an alcohol solvent (methanol or ethanol). Alcohol solvents (inparticular, methanol and ethanol) are preferable.

Examples of the base include alkali metal hydroxides (e.g., lithiumhydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide).Typically, alkali metal hydroxides can be used in the form of an aqueoussolution. Examples of the aqueous solution include sodium hydroxideaqueous solution.

The amount of the base for use is typically at least 1 mole, andpreferably about 1 to 5 moles, per mole of compound (6).

The reaction temperature is not particularly limited, and the reactioncan be typically performed under any of the following conditions: withcooling, at room temperature, or with heating. The reaction ispreferably performed at a temperature within the range of around roomtemperature to about 85° C. for 1 to 30 hours.

Production of Compound (11)

Compound (11) can be produced, for example, through the reaction stepsillustrated in the following reaction scheme.

Compound (7)→Compound (8)

Compound (8) can be produced by converting the hydroxy group of compound(7) into leaving group (X⁴).

Examples of the leaving group represented by X⁴ include halogen (e.g.,fluorine, chlorine, bromine, and iodine) and organic sulfonyloxy (e.g.,p-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy,nonafluorobutanesulfonyloxy, and o-nitrobenzolsulfonyloxy). Halogen ispreferable, and bromine is more preferable.

Compound (8′), wherein the leaving group represented by X⁴ is an organicsulfonyloxy, can be produced by reacting compound (7) with an organicsulfonyl halide or organic sulfonic acid anhydride containing theorganic sulfonyl group in a solvent in the presence of a base.

The solvent can be any solvent that does not adversely affect thereaction. Examples of the solvent include ketone solvents (e.g., acetoneand methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran,dioxane, diethyl ether, dimethoxyethane, and diglyme), ester solvents(e.g., methyl acetate and ethyl acetate), aprotic polar solvents (e.g.,acetonitrile, dimethylformamide, and dimethyl sulfoxide), halogenatedhydrocarbon solvents (e.g., methylene chloride and ethylene chloride),and combinations of these solvents. The solvent is preferably estersolvents (in particular, ethyl acetate etc.).

The base for use can be known inorganic bases or organic bases. Examplesof the inorganic bases include alkali metal hydrogen carbonates (e.g.,lithium hydrogen carbonate, sodium hydrogen carbonate, and potassiumhydrogen carbonate), alkali metal hydroxides (e.g., lithium hydroxide,sodium hydroxide, potassium hydroxide, and cesium hydroxide), alkalimetal carbonates (e.g., lithium carbonate, sodium carbonate, potassiumcarbonate, and cesium carbonate), and alkali metal hydrides (e.g.,sodium hydride and potassium hydride). The organic bases includetrialkyl amines (e.g., trimethylamine, triethylamine, andN,N-diisopropylethylamine), pyridine, quinoline, piperidine, imidazole,picoline, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylmorpholine, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),1,4-diazabicyclo[2.2.2]octane (DABCO), and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). When these bases are a liquid,these bases can also be used as a solvent. These bases can be usedsingly or in a combination of two or more. The base is preferablyN,N-diisopropylethylamine, and triethylamine, and more preferablyN,N-diisopropylethylamine. In particular, N,N-diisopropylethylamine ispreferable because the use of N,N-diisopropylethylamine cansignificantly increase the yield.

Examples of the organic sulfonyl halide include p-toluenesulfonylhalide, methanesulfonyl halide, trifluoromethanesulfonyl halide,nonafluorobutanesulfonyl halide, and o-nitrobenzolsulfonyl halide.Examples of the halide include chloride and bromide, with chloride beingpreferable. Particularly preferable organic sulfonyl halide includesmethanesulfonyl chloride.

Examples of the organic sulfonic acid anhydride includep-toluenesulfonic acid anhydride, methanesulfonic acid anhydride,trifluorosulfonic acid anhydride, nonafluorobutanesulfonic acidanhydride, and o-nitrobenzenesulfonic acid anhydride.

The amount of the base for use is typically 1 to 10 moles, andpreferably 1 to 6 moles, per mole of compound (7).

The amount of the organic sulfonyl halide or organic sulfonic acidanhydride for use is typically 1 to 5 moles, and preferably 1 to 2moles, per mole of compound (7).

The reaction temperature is not particularly limited, and the reactioncan be typically performed under any of the following conditions: withcooling, at room temperature, or with heating. The reaction ispreferably performed at a temperature of about 0 to 60° C. for 1 to 30hours.

The reaction described above produces compound (8′), wherein the leavinggroup represented by X⁴ is an organic sulfonyloxy.

Compound (8″), wherein the leaving group represented by X⁴ is halogen,can be produced by reacting compound (8′) with a halogenating agent in asolvent. When the leaving group represented by X⁴ is halogen, thehalogen includes fluorine, chlorine, bromine, and iodine, with chlorine,bromine, and iodine being preferable and chlorine being more preferable.

The solvent can be any solvent that does not adversely affect thereaction. Examples of the solvent include ketone solvents (e.g., acetoneand methyl ethyl ketone), ether solvents (e.g., tetrahydrofuran,dioxane, diethyl ether, dimethoxyethane, and diglyme), ester solvents(e.g., methyl acetate and ethyl acetate), aprotic polar solvents (e.g.,acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide),halogenated hydrocarbon solvents (e.g., methylene chloride and ethylenechloride), and combinations of these solvents.

Examples of the halogenating agent include alkali metal halides (e.g.,lithium chloride, lithium bromide, and lithium iodide), and quaternaryammonium halides (e.g., tetrabutylammonium chloride andtetrabutylammonium bromide). The halogenating agent is preferably analkali metal halide (in particular, lithium bromide).

The amount of the halogenating agent for use is typically 1 to 5 moles,and preferably 1 to 3 moles, per mole of compound (8′).

The reaction temperature is not particularly limited, and the reactioncan be typically performed under any of the following conditions: withcooling, at room temperature, or with heating. The reaction ispreferably performed at a temperature about 0 to 60° C. for 1 to 30hours.

The step of producing compound (8′) from compound (7) and the step ofproducing compound (8″) from compound (8′) are each independentlyperformed. Alternatively, both steps can be performed in one pot.

The obtained compound (8) (including compounds (8′) and (8″)) issubjected to the following reaction step.

Compound (8)→Compound (9)

Compound (9) can be produced by reacting compound (8) with a compoundrepresented by the following formula:

wherein M² represents an alkali metal (which may be hereinafter referredto as “phthalimide M² compound”). Examples of the alkali metalrepresented by M² include lithium, sodium, and potassium, with potassiumbeing preferable.

The reaction can be performed in a common solvent. The solvent can beany solvent that does not adversely affect the reaction. Examples of thesolvent include ketone solvents (e.g., acetone and methyl ethyl ketone),ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether,dimethoxyethane, and diglyme), ester solvents (e.g., methyl acetate andethyl acetate), aprotic polar solvents (e.g., acetonitrile,N,N-dimethylformamide, and dimethyl sulfoxide), halogenated hydrocarbonsolvents (e.g., methylene chloride and ethylene chloride), andcombinations of these solvents. The solvent is more preferablyN,N-dimethylformamide.

The proportion of compound (8) and phthalimide M² compound is typicallyat least 1 mole, and preferably about 1 to 5 moles of phthalimide M²compound, per mole of compound (8).

The reaction temperature is not particularly limited, and the reactioncan be typically performed under any of the following conditions: withcooling, at room temperature, or with heating. The reaction is performedat a temperature of about 0 to 100° C. for 1 to 30 hours.

Compound (9)→Compound (10)

Compound (10) can be produced by reacting compound (9) with methylamine.

The reaction can be performed in a common solvent. The solvent can beany solvent that does not adversely affect the reaction. Examples of thesolvent include water, alcohol solvents (e.g., methanol, ethanol,isopropanol, n-butanol, trifluoroethanol, and ethylene glycol), ethersolvents (e.g., tetrahydrofuran, dioxane, diethyl ether,dimethoxyethane, and diglyme), aprotic polar solvents (e.g.,acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide), andcombinations of these solvents. The solvent is preferably a combinationsolvent of water and an alcohol solvent (in particular, methanol orethanol).

Methylamine can be typically used in the form of a methylamine aqueoussolution.

The amount of methylamine for use is typically 1 to 10 moles, andpreferably 1 to 5 moles, per mole of compound (9).

The reaction temperature is not particularly limited, and the reactioncan be typically performed under any of the following conditions: withcooling, at room temperature, or with heating. The reaction ispreferably performed at a temperature within the range of around roomtemperature to about 100° C. for 10 minutes to 30 hours.

Obtained compound (10) is a primary amine compound. Compound (10) canoptionally be converted into a salt formed with an acid from thestandpoint of handleability. The salt can be formed in accordance with aknown method. The acid can be selected from a wide range of organicacids or inorganic acids. The organic acids include organic carboxylicacids, such as formic acid, acetic acid, lactic acid, tartaric acid, andsuccinic acid; and sulfonic acids, such as methanesulfonic acid,toluenesulfonic acid, and naphthalenesulfonic acid. Examples of theinorganic acids include hydrochloric acid, sulfuric acid, nitric acid,and phosphoric acid.

The solvent for use in forming the salt can be any solvent that does notadversely affect the reaction. Examples of the solvent include alcoholsolvents (e.g., methanol, ethanol, isopropanol, n-butanol,trifluoroethanol, and ethylene glycol), ketone solvents (e.g., acetoneand methyl ethyl ketone), ether solvents (e.g., cyclopentyl methyl ether(CPME), tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, anddiglyme), ester solvents (e.g., methyl acetate and ethyl acetate),aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide, anddimethyl sulfoxide), and combinations of these solvents. The solvent ispreferably ether solvents (in particular, CPME).

Compound (10)→Compound (11)

Compound (11) can be produced by subjecting compound (10) tocondensation reaction with 2-ethoxybenzoic acid.

The condensation reaction is typically performed in a solvent in thepresence of a condensation agent. When compound (10) is a salt formedwith an acid, compound (10) may be converted into a free primary amineby removing the acid from the salt using a base (e.g., inorganic bases,such as sodium hydroxide, potassium hydroxide, sodium carbonate, andsodium hydrogen carbonate; and organic bases, such as triethylamine andN,N-diisopropylethylamine) before performing the reaction.

The solvent can be any solvent that does not adversely affect thereaction. Examples of the solvent include halogenated aliphatichydrocarbon solvents (e.g., methylene chloride, chloroform, and ethylenechloride), ketone solvents (e.g., acetone and methyl ethyl ketone),ether solvents (e.g., tetrahydrofuran, dioxane, diethyl ether,dimethoxyethane, and diglyme), ester solvents (e.g., methyl acetate andethyl acetate), aromatic hydrocarbons (e.g., toluene and xylene),aprotic polar solvents (e.g., acetonitrile, N,N-dimethylformamide,N-methylpyrrolidone, and dimethyl sulfoxide), and combinations of thesesolvents. The solvent is preferably ketone solvents (in particular,acetone and methyl ethyl ketone), ether solvents (in particular,tetrahydrofuran, dioxane, diethyl ether, and dimethoxyethane), and estersolvents (e.g., methyl acetate and ethyl acetate).

Examples of the condensation agent include 1,1′-carbonyl diimidazole(CDI), dicyclohexyl carbodiimide (DCC), diisopropyl carbodiimide (DIC),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC orWSC), diphenylphosphoryl azide (DPPA),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium salts (e.g.,benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate), and 2-chloro-4,6-dimethoxytriazine (CDMT). Thecondensation agent is preferably CDI or WSC.

The amount of the condensation agent for use is typically at least 0.5moles, and preferably about 1 to 5 moles, per mole of 2-ethoxybenzoicacid.

Together with the condensation agent, an additive (activator), such as1-hydroxy benzotriazole (HOBt) or N-hydroxy succinimide (HOSu), canoptionally be used.

The amount of the additive for use is typically at least 1 mole, andpreferably about 1 to 5 moles, per mole of the condensation agent.

The reaction can be performed by optionally adding a base. Examples ofthe base include tertiary amines, such as triethylamine andN,N-diisopropylethylamine; and nitrogen-containing aromatic compounds,such aspyridine and 4-dimethylaminopyridine.

When a base is used, the amount of the base may be typically at least0.5 moles, and preferably about 1 to 5 moles, per mole of thecondensation agent.

The proportion of compound (10) and 2-ethoxybenzoic acid is typically atleast 1 mole, and preferably about 1 to 2 moles of 2-ethoxybenzoic acid,per mole of compound (10).

The reaction temperature is not particularly limited, and the reactioncan be typically performed under any of the following conditions: withcooling, at room temperature, or with heating. The reaction ispreferably performed at a temperature of about 0 to 100° C. for 1 to 30hours.

In this specification, the term “comprising” includes “consistingessentially of” and “consisting of.” The present invention covers allcombinations of the elements described in this specification.

EXAMPLES

The following describes the present invention in detail. However, thepresent invention is not limited to the Examples.

Production Example 1: Production 1 of Compound (3)

Compound (3) was produced in accordance with the following reactionscheme.

10.00 g (55.5 mmol) of compound (1a) and 9.20 g (66.6 mmol) of potassiumcarbonate were added to 40 ml of N,N-dimethylformamide and 6 ml ofwater, and the mixture was stirred until exotherm subsided. 16.92 g (111mmol) of sodium chlorodifluoroacetate was added thereto, and the mixturewas reacted at 95 to 110° C. for 3 hours. 80 ml of butyl acetate and 80ml of water were added to the reaction solution, and the solution waspartitioned. 80 ml of water was added again to the organic layer,followed by partitioning. 3 ml of concentrated hydrochloric acid wasadded to the organic layer, and the mixture was stirred at 60 to 70° C.for 30 minutes. 40 ml of water and 10 ml of a 25% sodium hydroxideaqueous solution were added to the reaction solution, and the mixturewas partitioned. 5.93 g (61.1 mmol) of sulfamic acid and 10 ml of waterwere added to the organic layer, and 22.08 g (61.0 mmol) of a 25% sodiumchlorite aqueous solution was added dropwise thereto at a temperature of20° C. or below. The mixture was reacted at 20° C. or below for 15minutes, and 10 ml of a 25% sodium hydroxide aqueous solution was addeddropwise thereto at a temperature of 20° C. or below, followed bypouring in 83.95 g (66.6 mmol) of a 10% sodium sulfite aqueous solution.Additionally, 2 ml of concentrated hydrochloric acid was added and themixture was partitioned, followed by concentration of the organic layerunder reduced pressure. 40 ml of methanol, 80 ml of water, and 10 ml ofa 25% sodium hydroxide aqueous solution were added to the concentratedresidue to dissolve the residue, and 5 ml of concentrated hydrochloricacid was added dropwise thereto to precipitate crystals. Theprecipitated crystals were collected by filtration and dried at 80° C.,thereby obtaining 11.81 g (yield: 86.4%) of compound (3) as a whitepowder.

¹H-NMR (CDCl₃) δ: 7.70 (2H, dd, J=6.4 Hz, 2.0 Hz), 7.22 (1H, d, J=9.2Hz), 6.66 (1H, t, J=74.8 Hz), 4.66 (1H, sept, J=6.0 Hz), 1.39 (6H, d,J=6.0 Hz).

Production Example 2: Production 2 of Compound (3)

Compound (3) was produced in accordance with the following reactionscheme.

10.00 g (53.2 mmol) of compound (1b), 9.55 g (69.1 mmol) of potassiumcarbonate, and 8.50 g (69.1 mmol) of isopropyl bromide were added to 40ml of N,N-dimethylformamide, and the mixture was reacted at 75 to 85° C.for 2 hours. 80 ml of butyl acetate and 80 ml of water were added to thereaction solution, and the mixture was partitioned. 5.68 g (58.5 mmol)of sulfamic acid and 10 ml of water were added to the organic layer, and21.15 g (58.5 mmol) of a 25% sodium chlorite aqueous solution was addeddropwise thereto at 20° C. or below, followed by reaction for 15minutes. 10 ml of a 25% sodium hydroxide aqueous solution was addedthereto at 20° C. or below, and subsequently 80.41 g (63.8 mmol) of a10% sodium sulfite aqueous solution was poured in. Additionally, 2 ml ofconcentrated hydrochloric acid was added, and the mixture waspartitioned, followed by concentration of the organic layer underreduced pressure. 40 ml of methanol, 80 ml of water, and 10 ml of a 25%sodium hydroxide aqueous solution were added to the concentratedresidue, and the residue was dissolved, followed by dropwise addition of5 ml of concentrated hydrochloric acid to precipitate crystals. Theprecipitated crystals were collected by filtration and dried at 80° C.,thereby obtaining 12.09 g (yield: 92.4%) of compound (3) as a whitepowder.

Production Example 3: Production of Compound (7)

Compound (7) was produced in accordance with the following reactionscheme.

Synthesis of Compound (4)

10.00 g (40.6 mmol) of compound (3) was added to 25 ml of acetonitrileat room temperature and stirred. 7.90 g (48.7 mmol) of carbonyldiimidazole was gradually added, and the mixture was reacted at roomtemperature for 1 hour. 10 ml (134 mmol) of 25% ammonia water was addedto 120 ml of water and cooled to 10° C. or below, followed by dropwiseaddition of the reaction solution thereto. The precipitated crystalswere collected by filtration and dried at 80° C., thereby obtaining 9.25g (yield: 92.9%) of compound (4) as a white powder.

¹H-NMR (CDCl₃) δ: 7.54 (1H, d, J=1.6 Hz), 7.25 (1H, dd, J=8.4 Hz, 2.0Hz), 7.17 (1H, d, J=8.0 Hz), 6.62 (1H, t, J=75.0), 5.96 (2H, br-d,J=75.2 Hz), 4.66 (1H, sept, J=6.13 Hz), 1.36 (6H, d, J=6.0 Hz).

Synthesis of Compound (5)

10.00 g (40.8 mmol) of compound (4) and 6.21 g (48.9 mmol) of1,3-dichloroacetone were added to 10 ml of toluene at room temperature,and the mixture was reacted under reflux for 3 hours. 60 ml of toluene,20 ml of water, and 2 ml of a 25% sodium hydroxide aqueous solution wereadded to the reaction solution, and the mixture was partitioned. Theorganic layer was concentrated under reduced pressure, thereby obtainingcompound (5) as a brownish solid (after recrystallization: fine yellowpowder).

¹H-NMR (CDCl₃) δ: 7.69 (1H, d, J=0.8 Hz), 7.64 (1H, d, J=2.0 Hz), 7.58(1H, dd, J=8.0 Hz, 1.6 Hz), 7.21 (1H, d, J=8.0 Hz), 6.61 (1H, t, J=75.0Hz), 4.69 (1H, sept, J=6.1 Hz), 4.56 (2H, s), 1.38 (6H, d, J=6.0 Hz).

Synthesis of Compound (7)

20 ml of N,N-dimethylformamide and 4.80 g (48.9 mmol) of potassiumacetate were added to the crude product of compound (5) obtained in thesection above, and the mixture was reacted at 90 to 100° C. for 3 hours.20 ml of methanol, 20 ml of water, and 5 ml of a 25% sodium hydroxideaqueous solution were added to the reaction solution, and reacted underreflux for 1 hour. 35 ml of water was added to the reaction solution,and the precipitated crystals were collected by filtration, followed bydrying at 80° C., thereby obtaining 10.33 g (yield: 84.6%) of compound(7) as a pale brownish powder.

¹H-NMR (CDCl₃) δ: 7.65-7.63 (2H, m), 7.57 (1H, dd, J=8.4 Hz, 2.0 Hz),7.21 (1H, d, J=8.0 Hz), 6.61 (1H, t, J=75.2 Hz), 4.70-4.66 (3H, m), 1.39(6H, d, J=6.0 Hz).

Production Example 4: Production of Compound (11)

Compound (11) was produced in accordance with the following reactionscheme.

Synthesis of Compound (9)

20.00 g (66.8 mmol) of compound (7) and 17.28 g (134 mmol) ofN,N-diisopropylethylamine were added to 300 ml of ethyl acetate, and themixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride waspoured in and stirred at 10 to 30° C. for 1 hour. 17.41 g (200 mmol) oflithium bromide was added thereto and reacted at 20 to 35° C. for 1hour. 100 ml of water was added to the reaction solution, and themixture was partitioned, followed by concentration of the organic layerunder reduced pressure. 300 ml of ethyl acetate was added to theconcentrated residue to dissolve the residue, and the solution was againconcentrated under reduced pressure. 200 ml of N,N-dimethylformamide and17.33 g (93.6 mmol) of potassium phthalimide were added to theconcentrated residue and reacted at 75 to 85° C. for 1 hour. 200 ml ofwater was added to the reaction solution to precipitate crystals. Theprecipitated crystals were collected by filtration and dried at 80° C.,thereby obtaining 25.90 g (yield: 90.5%) of compound (9) as a whitepowder.

¹H-NMR (DMSO-d₆) δ: 8.22 (1H, s), 7.94-7.86 (4H, m), 7.58 (1H, d, J=2.0Hz), 7.52 (1H, dd, J=8.8 Hz, 2.4 Hz), 7.30 (1H, d, J=8.4 Hz), 7.14 (1H,t, J=74.2 Hz), 4.78-4.69 (3H, m), 1.30 (6H, d, J=6.0 Hz).

Synthesis of Compound (10)

15.00 g (35.0 mmol) of compound (9) was mixed with 30 ml of a 40%methylamine aqueous solution, 30 ml of methanol, and 75 ml of water, andreacted under reflux for 30 minutes. 150 ml of cyclopentyl methyl ether(CPME) and 15 ml of a 25% sodium hydroxide aqueous solution were addedto the reaction solution, and the temperature was adjusted to 65 to 75°C., followed by partitioning. A mixture of 150 ml of water and 7.50 g ofsodium chloride was added to the organic layer, and the temperature wasadjusted to 65 to 75° C. again, followed by partitioning. 3.75 ml ofconcentrated hydrochloric acid was added to the organic layer toprecipitate crystals. The precipitated crystals were collected byfiltration and dried at 60° C., thereby obtaining 11.95 g (yield:quant.) of compound (10) as a white powder.

¹H-NMR (DMSO-d₆) δ: 8.51 (3H, br-s), 8.29 (1H, s), 7.64 (1H, d, J=2 Hz),7.59 (1H, dd, J=8.0 Hz, 1.6 Hz), 7.37 (1H, d, J=8.4 Hz), 7.18 (1H, t,J=74.0 Hz), 4.72 (1H, sept, J=6.1 Hz), 4.03 (2H, s), 1.33 (6H, d, J=6.4Hz).

Synthesis of Compound (11)

13.30 g (39.7 mmol) of compound (10) was mixed with 3.83 g (37.8 mmol)of triethylamine and 108 ml of ethyl acetate, and stirred at 20 to 30°C. for 1 hour. 9.78 g (58.9 mmol) of 2-ethoxybenzoic acid and 11.28 g(58.8 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (WSC) were added to the reaction solution, and reacted at20 to 30° C. for 1 hour. 54 ml of water and 5.4 ml of concentratedhydrochloric acid were added to the reaction solution, and thetemperature was adjusted to 40 to 50° C., followed by partitioning. 54ml of water and 5.4 ml of a 25% sodium hydroxide aqueous solution wereadded to the organic layer, and the temperature was adjusted to 40 to50° C. again. The mixture was partitioned, and the organic layer wasconcentrated under reduced pressure. 45 ml of ethanol, 18 ml of water,5.4 ml of a 25% sodium hydroxide aqueous solution, and 0.54 g ofactivated carbon were added to the concentrated residue, and the mixturewas refluxed for 30 minutes. The activated carbon was removed byfiltration, and the filtrate was washed with 11 ml of ethanol. Thefiltrate was cooled, and a seed crystal was added thereto to precipitatecrystals. The precipitated crystals were collected by filtration anddried at 35° C., thereby obtaining 12.88 g (72.6%) of compound (11) as awhite powder.

¹H-NMR (CDCl₃) δ: 8.56 (1H, br-s), 8.23 (1H, dd, J=7.6 Hz, 1.6 Hz), 7.66(1H, s), 7.63 (1H, d, J=2.0 Hz), 7.58 (1H, dd, J=8.4 Hz, 2.0 Hz),7.44-7.39 (1H, m), 7.21 (1H, d, J=8.0 Hz), 7.08-7.04 (1H, mH), 6.94 (1H,d, J=8.0 Hz), 6.61 (1H, t, J=75.2 Hz), 4.68 (1H, sept, J=6.0 Hz), 4.62(2H, d, J=6.0 Hz), 4.17 (2H, q, J=6.93), 1.48 (3H, t, J=7.2 Hz), 1.39(6H, d, J=5.6 Hz).

Production Example 5: Production of Compounds (i) to (ix)

The compounds shown in the following Table 2 were produced as describedbelow. The ¹H-NMR of the produced compounds is also shown below.Compound (ii) is the same as compound (9).

TABLE 2 Formula Number Structural Formula i

ii

iii

iv

v

vi

vii

viii

ix

Synthesis of Compound (i)

13.1 g of2-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]isoindoline-1,3-dione(2-((2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methyl)isoindoline-1,3-dione)synthesized in accordance with the synthesis procedure described in PTL2 (WO2014/034958 pamphlet) was dissolved in a mixture of 260 ml ofethanol and 140 ml of DMF, and 1.3 g of a 10% palladium carbon powderwas added thereto, followed by stirring in a hydrogen atmosphere at 40°C. for 1 hour. 100 ml of methylene chloride was added to the reactionsolution and stirred, followed by removal of the catalyst by filtration.The crude crystals obtained by concentrating the filtrate wererecrystallized from ethyl acetate, thereby obtaining 8.8 g of2-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-ylmethyl]isoindoline-1,3-dione(2-((2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazol-4-yl)methyl)isoindoline-1,3-dione:compound (i)) as a white powder.

¹H-NMR (CDCl₃) δ: 8.18 (1H, br-s) 7.85-8.17 (5H, m) 6.89-7.51 (4H, m)4.74 (2H, s).

Synthesis of Compound (ii)

2 g of compound (i) and 3.9 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene(DBU) were dissolved in 20 ml of ethanol, and 3.18 g of isopropylbromide was added thereto, followed by heating under reflux overnight.Subsequently, 1 ml of a 10% sodium hydroxide aqueous solution was addedto the reaction solution, and the mixture was heated under reflux for 30minutes. Ice water was added to the reaction solution, followed byextraction with ethyl acetate. The organic layer was washed with watertwice, and concentrated under reduced pressure, thereby obtaining[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]isoindoline-1,3-dione(2-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)isoindoline-1,3-dione:compound (ii)).

¹H-NMR (CDCl₃) δ: 7.85-7.92 (2H, m) 7.71-7.77 (2H, m) 7.68 (1H, s) 7.61(1H, d, J=2.1 Hz) 7.55 (1H, dd, J=8.4 Hz, 2.1 Hz) 7.18 (1H, d, J=8.4 Hz)6.60 (1H, t, J=75 Hz) 4.86 (2H, d, J=1.2 Hz) 4.68 (1H, sept, J=6.0 Hz)1.38 (6H, d, J=6.0 Hz).

Synthesis of Compound (iii)

1.58 g of compound (ii) was dissolved in 16 ml of methanol, and 3.2 mlof a methylamine aqueous solution (40%) was added thereto, followed byheating under reflux for 1 hour. The reaction solution was concentrated,and the reaction product was dissolved in ethyl acetate, followed bywashing of the organic layer with a 10% sodium hydroxide aqueoussolution and water. The organic layer was separated and concentratedunder reduced pressure, thereby obtaining 1.17 g of[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-yl]methylamine((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methanamine:compound (iii)) as a brownish solid.

¹H-NMR (CDCl₃) δ: 7.65 (1H, d, J=1.8 Hz) 7.58 (1H, d, J=8.4 Hz, 1.8 Hz)7.55 (1H, s) 7.22 (1H, d, J=8.4 Hz) 6.62 (1H, t, J=75 Hz) 4.70 (1H,sept, J=6.3 Hz) 3.85 (2H, s) 1.40 (6H, d, J=6.3 Hz).

Synthesis of Compound (iv)

0.24 g of 5-benzyloxy-2-ethoxybenzoic acid and 0.44 g of compound (iii)were suspended in 20 ml of acetone, and 0.27 g of 1-hydroxybenzotriazole (HOBt) and 0.38 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) wereadded thereto, followed by heating under reflux for 1 hour. The reactionsolution was cooled, and acetone was evaporated under reduced pressure,followed by addition of water to the residue and extraction with ethylacetate. The organic layer was washed with water twice and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=3:1). The obtained crudecrystals were recrystallized from n-hexane:ethyl acetate, therebyobtaining 0.28 g ofN-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-5-benzyloxy-2-ethoxybenzamide(5-(benzyloxy)-N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-ethoxybenzamide:compound (iv)) as a white powder.

¹H-NMR (CDCl₃) δ: 8.68 (1H, br-s), 7.76 (1H, d, J=3 Hz), 7.66-7.57 (3H,m), 7.38-7.20 (6H, m), 6.97 (1H, dd, J=3.3, 8.7 Hz), 6.62 (1H, t, J=75Hz), 4.71-4.61 (4H, m), 4.05 (2H, q, J=6.9 Hz), 1.57-1.37 (9H, m).

Synthesis of Compound (v)

5.5 g of[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-yl]methylamine(2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methanamine(MAP-15211) synthesized in accordance with the synthesis proceduredescribed in PTL 2 (WO2014/034958 pamphlet) and 3.4 g of acetylsalicylicacid were suspended in 150 ml of acetone. 3.4 g of 1-hydroxybenzotriazole (HOBt) and 4.8 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) wereadded thereto, followed by heating under reflux for 1 hour.Subsequently, 10 ml of a 10% sodium hydroxide aqueous solution was addedthereto, and the mixture was heated under reflux for 30 minutes. Thereaction solution was then cooled, and acetone was evaporated underreduced pressure. Water was added to the residue and extraction wasperformed with ethyl acetate. The organic layer was washed with watertwice and concentrated under reduced pressure, thereby obtaining 3.1 gofN-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-hydroxybenzamide(N-((2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methyl)-2-hydroxybenzamide:compound (v)) as a white powder.

¹H-NMR (CDCl₃) δ: 12.19 (1H, s) 7.70-7.72 (2H, m), 7.63 (1H, dd, J=8.4,1.8 Hz), 7.28-7.51 (7H, m), 7.22-7.26 (2H, m), 6.98-7.01 (1H, m),6.82-6.88 (2H, m), 6.63 (1H, t, J=74.7 Hz), 5.22 (2H, s), 4.60 (2H, dd,J=5.4, 0.9 Hz).

Synthesis of Compound (vi)

3.1 g of compound (v) was dissolved in 45 ml of N,N-dimethylformamide,and 1.7 g of 2-bromoethyl acetate and 1.8 g of potassium carbonate wereadded thereto, followed by heating with stirring at 80° C. for 1 hour.Ice water was added to the reaction solution, and extraction wasperformed with ethyl acetate. The organic layer was washed with watertwice and concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (ethylacetate:n-hexane=1:1), thereby obtaining 3.6 g ofN-[2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-[(2-acetoxy)ethoxy]benzamide(2-(2-((2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methylcarbamoyl)phenoxy)ethylacetate: compound (vi)) as a white powder.

1H-NMR (CDCl₃) δ: 8.43 (1H, br-s) 8.25 (1H, d, J=8.4 Hz), 7.73 (1H, d,J=1.8 Hz), 7.68 (1H, s), 7.62 (1H, dd, J=5.4, 1.8 Hz), 7.34-7.49 (6H,m), 7.24-7.26 (1H, m), 7.09-7.15 (1H, m), 6.93 (1H, d, J=7.8 Hz), 6.63(1H, t, J=74.4 Hz), 5.22 (2H, s), 4.65 (2H, d, J=5.7 Hz), 4.50-4.53 (2H,m), 4.27-4.32 (2H, m), 2.03 (3H, s).

Synthesis of Compound (vii)

3.5 g of compound (vi) was suspended in 100 ml of ethanol, and 0.4 g ofa 10% palladium carbon powder was added thereto, followed by stirring ina hydrogen atmosphere at room temperature for 4 hours. The catalyst wasremoved by filtration, and the crude crystals obtained by concentratingthe filtrate were recrystallized from ethanol-n-hexane, therebyobtaining 2.1 g ofN-[2-(3-hydroxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-[(2-acetoxy)ethoxy]benzamide(2-(2-((2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazol-4-yl)methylcarbamoyl)phenoxy)ethylacetate: compound (vii)) as a white powder.

¹H-NMR (CDCl₃) δ: 8.45 (1H, br-s), 8.25 (1H, d, J=8.4 Hz), 7.76 (1H, s),7.66 (1H, s), 7.42-7.53 (2H, m), 7.09-7.26 (3H, m), 6.95 (1H, d, J=7.8Hz), 6.78 (1H, br-s), 6.64 (1H, t, J=74.1 Hz), 4.58-4.65 (4H, m),4.31-4.34 (2H, m), 2.11 (2H, s).

Synthesis of Compound (viii)

5.1 g of methyl pyruvate and 0.8 ml of bromine were dissolved in 15 mlof 1,2-dimethoxyethane, and the solution was heated with stirring at 50°C. for 1 hour. The reaction solution was concentrated, and the residuewas dissolved in 45 ml of 2-methoxy ethanol. 3 g of3-benzyloxy-4-difluoromethoxybenzamide(3-(benzyloxy)-4-(difluoromethoxy)benzamide) synthesized in accordancewith the synthesis procedure described in PTL 1 (WO2007/058338 pamphlet)was added thereto and heated under reflux for 4 hours. 25 ml of waterwas added to the reaction solution and stirred at room temperatureovernight. The precipitated crystals were collected by filtration anddried under reduced pressure at room temperature, thereby obtaining 0.73g of methyl 2-(3-benzyloxy-4-difluoromethoxyphenyl)oxazole-4-carboxylate(methyl2-(3-(benzyloxy)-4-(difluoromethoxy)phenyl)oxazole-4-carboxylate:compound (viii)) as white crystals.

¹H-NMR (CDCl₃) δ: 8.29 (1H, s) 7.84 (1H, d, J=2.1 Hz) 7.71 (1H, dd,J=8.4 Hz, 1.8 Hz) 7.35-7.48 (6H, m) 6.64 (1H, t, J=75 Hz) 5.22 (2H, s)3.97 (3H, s).

Synthesis of Compound (ix)

0.28 g of compound (viii) was dissolved in 5 ml of ethanol, 1 ml oftetrahydrofuran, and 0.5 ml of N,N-dimethylformamide, and 0.03 g of a10% palladium carbon powder was added thereto, followed by stirring in ahydrogen atmosphere at room temperature for 2 hours. The catalyst wasremoved by filtration, and the filtrate was concentrated under reducedpressure. Water was added to the residue, and extraction was performedwith ethyl acetate. The organic layer was washed with a saturated sodiumchloride solution one time and concentrated under reduced pressure,thereby obtaining 0.18 g of methyl2-(3-hydroxy-4-difluoromethoxyphenyl)oxazole-4-carboxylate (methyl2-(4-(difluoromethoxy)-3-hydroxyphenyl)oxazole-4-carboxylate: compound(ix)) as white crystals.

¹H-NMR (CDCl₃) δ: 8.28 (1H, s), 7.77 (1H, d, J=1.8 Hz), 7.68 (1H, dd,J=8.4, 1.8 Hz), 7.21 (1H, d, J=8.4 Hz), 6.61 (1H, t, J=72.9 Hz), 5.57(1H, s), 3.96 (3H, s).

Production Example 6: Production of Compounds (11a) to (11s)

The compounds shown in the following Table 3 were produced as describedbelow. The ¹H-NMR of the produced compounds is also shown below.

TABLE 3 Formula Number Structural Formula 11a

11b

11c

11d

11e

11f

11g

11h

11i

11j

11k

11l

11m

11n

11o

11p

11q

11r

11s

Synthesis of Compound (11a)

3 g of compound (iii) and 1.5 g of salicylic acid were suspended in 60ml of acetone, and 1.8 g of 1-hydroxy benzotriazole (HOBt) and 2.6 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) wereadded thereto, followed by heating under reflux for 1 hour. The reactionsolution was cooled, and acetone was evaporated under reduced pressure.Water was added to the residue, and extraction was performed with ethylacetate. The organic layer was washed with water twice and concentratedunder reduced pressure. The obtained crude crystals were recrystallizedfrom ethyl acetate-n-hexane, thereby obtaining 1.47 g ofN-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-hydroxybenzamide(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-hydroxybenzamide:compound (11a)) as a white powder.

¹H-NMR (CDCl₃) δ: 12.19 (1H, s), 7.70 (1H, s), 7.50-7.64 (2H, m),7.37-7.42 (2H, m), 7.23 (1H, d, J=8.4 Hz), 6.81-7.01 (3H, m), 6.63 (1H,t, J=75.0 Hz), 4.69 (1H, sept., J=6.0 Hz), 4.59 (2H, d, J=5.4 Hz), 1.40(6H, d, J=6.0 Hz).

Synthesis of Compound (11b)

The procedure in “Synthesis of Compound (11a)” above was repeated using0.44 g of compound (iii) and 0.24 g of 2-ethoxy-3-hydroxy benzoic acid,thereby obtaining 0.28 g ofN-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy-3-hydroxybenzamide(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-ethoxy-3-hydroxybenzamide:compound (11b)) as a white powder.

¹H-NMR (CDCl₃) δ: 7.97 (1H, br-t, J=5.1 Hz), 7.70 (1H, s), 7.64 (1H, d,J=1.8 Hz), 7.52-7.60 (3H, m), 7.23 (1H, d, J=8.4 Hz), 7.10 (1H, d, J=2.4Hz), 7.09 (1H, s), 6.63 (1H, t, J=75.0 Hz), 4.64-4.72 (1H, m), 4.61 (2H,d, J=5.1 Hz), 4.00 (2H, q, J=6.9 Hz), 1.38 (3H, t, J=6.9 Hz).

Synthesis of Compound (11c)

The procedure in “Synthesis of Compound (11a)” above was repeated usingcompound (iv), thereby obtaining 5 mg ofN-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy-5-hydroxybenzamide(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-ethoxy-5-hydroxybenzamide:compound (11c)) as a white powder.

¹H-NMR (CDCl₃) δ: 8.83 (1H, br), 8.04 (1H, d, J=3.3 Hz), 7.69 (1H, s),7.64 (1H, d, J=1.8 Hz), 7.58 (1H, dd, J=1.8, 8.4 Hz), 7.21 (1H, d, J=5.1Hz), 6.87-6.99 (3H, m), 6.62 (1H, t, J=75 Hz), 4.61-4.72 (3H, m), 4.12(2H, q, J=6.9 Hz), 1.38-1.47 (9H, m)

Synthesis of Compound (11d)

0.1 g of compound (11a) was dissolved in 3 ml of N,N-dimethylformamide,and 0.12 g of 2-bromoethyl acetate and 0.14 g of potassium carbonatewere added thereto, followed by heating with stirring at 80° C. for 2hours. Subsequently, 1 ml of methanol and 0.3 ml of a 25% sodiumhydroxide aqueous solution were added to the reaction solution, and themixture was heated under reflux for 1 hour. Ice water was added to thereaction solution, and extraction was performed with ethyl acetate. Theorganic layer was washed with water twice and concentrated under reducedpressure. The obtained residue was recrystallized from ethylacetate-n-hexane, thereby obtaining 70 mg ofN-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-hydroxyethoxy)benzamide(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-(2-hydroxyethoxy)benzamide:compound (11d)) as a white powder.

¹H-NMR (CDCl₃) δ: 8.67 (1H, br-s) 8.16 (1H, dd, J=7.8, 1.8 Hz),7.70-7.74 (2H, m), 7.62 (1H, dd, J=8.4, 1.8 Hz), 7.40-7.46 (1H, m),7.24-7.26 (1H, m), 7.06-7.12 (1H, m), 6.94-6.97 (1H, m), 6.65 (1H, t,J=75.0 Hz), 5.43 (1H, t, J=6.6 Hz), 4.69-4.77 (1H, m), 4.62 (2H, d,J=5.4 Hz), 4.18-4.21 (2H, m), 3.94-3.99 (2H, m), 1.42 (6H, d, J=6.3 Hz).

Synthesis of Compound (11e)

0.3 g of compound (vii) and 0.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene(DBU) were dissolved in 4 ml of ethanol, and 0.31 g of ethyl iodide wasadded thereto, followed by heating under reflux overnight. Subsequently,1 ml of a 10% sodium hydroxide aqueous solution was added to thereaction solution, and heated under reflux for 30 minutes. Thereafter,ice water was added to the reaction solution, and extraction wasperformed with ethyl acetate. The organic layer was washed with watertwice and concentrated under reduced pressure. The obtained crudecrystals were recrystallized from ethanol-n-hexane, thereby obtaining 95mg ofN-[2-(3-ethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-hydroxyethoxy)benzamideN-((2-(4-(difluoromethoxy)-3-ethoxyphenyl)oxazol-4-yl)methyl)-2-(2-hydroxyethoxy)benzamide(OPA-15566) as a white powder.

¹H-NMR (CDCl₃) δ: 8.86 (1H, br-s) 8.15 (1H, dd, J=8.1, 1.8 Hz), 7.74(1H, d, J=2.1 Hz), 7.70 (1H, s), 7.63 (1H, dd, J=8.1, 2.1 Hz), 7.40-7.46(2H, m), 7.06-7.09 (1H, m), 6.90-6.96 (1H, m), 6.66 (1H, t, J=74.7 Hz),5.45 (1H, brs), 4.62 (2H, d, J=5.4 Hz), 4.22 (2H, q, J=6.9 Hz), 4.19(2H, dd, J=4.5, 4.2 Hz), 3.97 (2H, dd, J=4.5, 4.2 Hz), 1.50 (3H, t,J=6.9 Hz)

Synthesis of Compound (11f)

0.3 g of compound (vii) and 0.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene(DBU) were dissolved in ethanol, and 0.27 g of (bromomethyl)cyclopropanewas added thereto, followed by heating under reflux overnight.Subsequently, 1 ml of a 10% sodium hydroxide aqueous solution was addedto the reaction solution, and heated under reflux for 30 minutes. Icewater was then added to the reaction solution, and extraction wasperformed with ethyl acetate. The organic layer was washed with watertwice and concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (methylene chloride). Theobtained crude crystals were recrystallized from ethyl acetate-n-hexane,thereby obtaining 0.26 g of N-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-hydroxyethoxy)benzamide(N-((2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methyl)-2-(2-hydroxyethoxy)benzamide:compound (11f)) as a white powder.

¹H-NMR (CDCl₃) δ: 8.85 (1H, br-s) 8.16 (1H, dd, J=7.5, 1.8 Hz),7.61-7.73 (2H, m), 7.40-7.46 (1H, m), 7.24-7.27 (1H, m), 7.06-7.12 (1H,m), 6.72 (1H, t, J=74.7 Hz), 5.37-5.42 (1H, m), 4.18-4.21 (2H, m),3.94-4.01 (4H, m), 1.32-1.37 (1H, m), 0.65-0.71 (2H, m), 0.37-042 (2H,m).

Synthesis of Compound (11g)

0.3 g of compound (vii) and 0.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene(DBU) were dissolved in ethanol, and 0.28 g of isobutyl bromide wasadded thereto, followed by heating under reflux overnight. Subsequently,1 ml of a 10% sodium hydroxide aqueous solution was added to thereaction solution and heated under reflux for 30 minutes. Ice water wasthen added to the reaction solution, and extraction was performed withethyl acetate. The organic layer was washed with water twice andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (methylene chloride). The obtainedcrude crystals were recrystallized from ethyl acetate-n-hexane, therebyobtaining 0.15 g ofN-[2-(3-isobutoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-hydroxyethoxy)benzamide(N-((2-(4-(difluoromethoxy)-3-isobutoxyphenyl)oxazol-4-yl)methyl)-2-(2-hydroxyethoxy)benzamide:compound (11g)) as a white powder.

¹H-NMR (CDCl₃) δ: 8.86 (1H, br-s) 8.16 (1H, dd, J=7.8, 1.8 Hz),7.70-7.74 (2H, m), 7.61-7.64 (1H, m), 7.40-7.46 (1H, m), 7.24-7.26 (1H,m), 6.97-6.90 (1H, m), 6.64 (1H, t, J=75.0 Hz), 5.40 (1H, t, J=6.6 Hz),4.62 (2H, d, J=5.4 Hz), 4.18-4.22 (2H, m), 3.90-4.00 (4H, m), 2.11-2.25(1H, m), 1.08 (6H, d, J=6.9 Hz).

Synthesis of Compound (11h)

0.3 g of compound (vii) and 0.3 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene(DBU) were dissolved in ethanol, and 0.3 g of (bromomethyl)cyclobutanewas added thereto, followed by heating under reflux overnight.Subsequently, 1 ml of a 10% sodium hydroxide aqueous solution was addedto the reaction solution and heated under reflux for 30 minutes. Icewater was then added to the reaction solution, and extraction wasperformed with ethyl acetate. The organic layer was washed with watertwice and concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (methylene chloride). Theobtained crude crystals were recrystallized from ethyl acetate-n-hexane,thereby obtaining 0.24 g ofN-[2-(3-cyclobutylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(2-hydroxyethoxy)benzamide(N-((2-(3-(cyclobutylmethoxy)-4-(difluoromethoxy)phenyl)oxazol-4-yl)methyl)-2-(2-hydroxyethoxy)benzamide: compound (11h)) as a white powder.

¹H-NMR (CDCl₃) δ: 8.86 (1H, br-s) 8.16 (1H, dd, J=7.8, 1.8 Hz), 7.63(1H, dd, J=8.4, 2.1 Hz), 7.70-7.74 (2H, m), 7.40-7.46 (1H, m), 7.23-7.26(1H, m), 7.07-7.12 (1H, m), 6.95 (1H, d, J=7.8 Hz), 6.65 (1H, t, J=75.3Hz), 5.41 (1H, t, J=6.6 Hz), 4.62 (2H, d, J=5.4 Hz), 4.20 (2H, dd,J=4.5, 4.2 Hz), 4.11 (2H, d, J=6.6 Hz), 3.96-4.01 (2H, m), 2.80-2.90(1H, m), 2.13-2.20 (2H, m), 1.88-2.02 (4H, m).

Synthesis of Compound (11i)

0.28 g of compound (iii) and 0.17 g of 2,3-dihydroxy benzoic acid weresuspended in 3 ml of acetone, and 0.17 g of 1-hydroxy benzotriazole(HOBt) and 0.23 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (WSC) were added thereto, followed by heating under refluxfor 3 hours. The reaction solution was cooled, and acetone wasevaporated under reduced pressure. Water was added to the residue, andextraction was performed with ethyl acetate. The organic layer waswashed with water twice and concentrated under reduced pressure. Theobtained residue was partially purified by silica gel columnchromatography (dichloromethane:methanol=50:1). The obtained crudecrystals were recrystallized from n-hexane-acetone, thereby obtaining0.2 g ofN-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2,3-dihydroxybenzamide(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2,3-dihydroxybenzamide:compound (11i)) as a white powder.

¹H-NMR (DMSO) δ: 12.54 (1H, s), 9.30 (1H, br-t, J=5.4 Hz), 9.23 (1H, s),8.12 (1H, s), 7.61 (1H, d, J=1.8 Hz), 7.55 (1H, dd, J=8.4, 1.8 Hz),7.38-7.28 (2H, m), 7.15 (1H, t, J=74.1 Hz), 6.95-6.89 (1H, m), 6.69 (1H,t, J=8.1 Hz), 4.74 (1H, sept., J=6.0 Hz), 4.45 (2H, d, J=5.4 Hz), 1.32(6H, d, J=6.0 Hz).

Synthesis of Compound (11j)

The procedure in “Synthesis of Compound (11i)” above was repeated using0.28 g of compound (iii) and 0.17 g of 2,4-dihydroxybenzoic acid,thereby obtaining 0.17 g ofN-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2,4-dihydroxybenzamide(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2,4-dihydroxybenzamide:compound (11j)) as a white powder.

¹H-NMR (DMSO) δ: 12.75 (1H, s), 10.11 (1H, s), 9.05 (1H, br-t, J=5.4Hz), 8.10 (1H, s), 7.74 (1H, d, J=8.7 Hz), 7.61 (1H, d, J=1.8 Hz), 7.55(1H, dd, J=8.4, 1.8 Hz), 7.32 (1H, d, J=8.4 Hz), 7.16 (1H, t, J=74.1Hz), 6.29 (1H, dd, J=8.7 Hz, 2.4 Hz), 6.24 (1H, d, J=2.4 Hz), 4.74 (1H,sept., J=6.0 Hz), 4.42 (2H, d, J=5.7 Hz), 1.32 (6H, d, J=6.0 Hz).

Synthesis of Compound (11k)

The procedure in “Synthesis of Compound (11i)” above was repeated using0.28 g of compound (iii) and 0.17 g of 2,5-dihydroxybenzoic acid,thereby obtaining 0.16 g ofN-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2,5-dihydroxybenzamide(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2,5-dihydroxybenzamide:compound (11k)) as a white powder.

¹H-NMR (DMSO) δ: 11.47 (1H, s), 9.14 (1H, br-t, J=5.4 Hz), 8.98 (1H, s),8.08 (1H, s), 7.61 (1H, d, J=1.8 Hz), 7.55 (1H, dd, J=8.4, 1.8 Hz), 7.31(1H, d, J=8.4 Hz), 7.29 (1H, d, J=3.0 Hz), 7.14 (1H, t, J=74.1 Hz), 6.86(1H, dd, J=8.7 Hz), 6.74 (1H, d, J=8.7 Hz), 4.74 (1H, sept., J=6.0 Hz),4.44 (2H, d, J=5.1 Hz), 1.31 (6H, d, J=6.0 Hz).

Synthesis of Compound (11l)

The procedure in “Synthesis of Compound (11i)” above was repeated using0.28 g of compound (iii) and 0.17 g of 2,6-dihydroxybenzoic acid,thereby obtaining 0.2 g ofN-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2,6-dihydroxybenzamide(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2,6-dihydroxybenzamide:compound (11l)) as a white powder.

¹H-NMR (DMSO) δ: 12.51 (1H, s), 9.32 (1H, br-t, J=5.4 Hz), 8.11 (1H, s),7.62 (1H, d, J=1.8 Hz), 7.56 (1H, dd, J=8.4, 1.8 Hz), 7.32 (1H, d, J=8.4Hz), 7.18 (1H, t, J=8.1 Hz), 7.14 (1H, t, J=74.1 Hz), 6.37 (2H, d, J=8.1Hz), 4.74 (1H, sept., J=6.0 Hz), 4.52 (2H, d, J=5.4 Hz), 1.32 (6H, d,J=6.0 Hz).

Synthesis of Compound (11m)

0.2 g of compound (11a) was dissolved in 2 ml of acetonitrile. 0.23 g ofsodium iodide, 0.27 g of potassium carbonate, and 98 mg of3-chloropropyl acetate were added thereto, followed by heating underreflux overnight. 2 ml of a 10% sodium hydroxide aqueous solution wasfurther added thereto, and the mixture was heated under reflux until thereaction was completed. After cooling, water was added to the reactionsolution, and extraction was performed with ethyl acetate. The organiclayer was washed with water twice and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1), and the obtained crudecrystals were recrystallized from ethanol-n-hexane, thereby obtaining0.15 g ofN-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-(3-hydroxypropoxyy)benzamide(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-(3-hydroxypropoxy)benzamide:compound (11m)) as a white powder.

¹H-NMR (CDCl₃) δ: 9.11 (1H, br-t, J=6.0 Hz), 8.21 (1H, dd, J=8.4, 1.8Hz), 7.72 (1H, s), 7.61 (1H, d, J=1.8 Hz), 7.57 (1H, dd, J=8.4, 1.8 Hz),7.38-7.44 (1H, m), 7.26-7.23 (1H, m), 7.03-7.08 (1H, m), 6.96 (1H, d,J=8.4 Hz), 6.63 (1H, t, J=75.0 Hz), 4.69 (1H, sept., J=6.0 Hz), 4.59(2H, d, J=6.0 Hz), 4.29 (2H, t, J=5.4 Hz), 3.89-3.94 (2H, m), 2.07-2.13(2H, m), 1.41 (6H, d, J=6.0 Hz).

Synthesis of Compound (11n)

0.18 g of compound (ix) was dissolved in 2 ml of N,N-dimethylformamide,and 0.18 g of potassium carbonate and 0.12 ml of isopropyl bromide wereadded thereto, followed by stirring at room temperature for 16 hours andat 45° C. for 4 hours. Water was added thereto with ice cooling, andextraction was performed with ethyl acetate. The organic layer waswashed with a saturated sodium chloride solution one time andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (n-hexane:ethyl acetate=2:1),thereby obtaining 0.16 g of methyl2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazole-4-carboxylate (methyl2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazole-4-carboxylate:compound (11n)) as a white powder.

¹H-NMR (CDCl₃) δ: 8.28 (1H, s), 7.74 (1H, d, J=1.8 Hz), 7.66 (1H, dd,J=8.4, 1.8 Hz), 7.25 (1H, d, J=8.4 Hz), 6.63 (1H, t, J=74.7 Hz), 4.71(1H, sept., J=6.0 Hz), 3.96 (3H, s), 1.39 (6H, d, J=6.0 Hz).

Synthesis of Compound (11o)

0.7 g of compound (11n) was dissolved in 7 ml of methanol, and 1.4 ml ofa 25% sodium hydroxide aqueous solution was added thereto, followed byheating under reflux at room temperature for 30 minutes. The reactionsolution was stirred with ice cooling, and concentrated hydrochloricacid was added thereto to give a pH of 3, followed by collection of theprecipitated crystals by filtration. The obtained crystals were driedunder reduced pressure, thereby obtaining2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazole-4-carboxylic acid(2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazole-4-carboxylic acid:compound (11o)).

¹H-NMR (CDCl₃) δ: 8.38 (1H, s), 7.74 (1H, d, J=1.8 Hz), 7.66 (1H, dd,J=8.1 Hz, 1.8 Hz), 7.25 (1H, d, J=8.1 Hz), 6.64 (1H, t, J=75 Hz), 4.72(1H, sept, J=6.3 Hz), 1.40 (6H, d, J=6.3 Hz).

Synthesis of Compound (11p)

The procedure in “Synthesis of Compound (11i)” above was repeated usingcompound (iii) and 2-ethoxy-6-hydroxy benzoic acid, thereby obtainingN-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy-6-hydroxybenzamide(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-ethoxy-6-hydroxybenzamide:compound (11p)).

¹H-NMR (CDCl₃) δ: 13.81 (1H, s), 9.00 (1H, brs), 7.68-7.62 (2H, m), 7.60(1H, dd, J=8.4 Hz, 2.1 Hz), 7.30-7.18 (2H, m), 6.63 (1H, t, J=75 Hz),6.61 (1H, d, J=8.4 Hz), 6.37 (1H, d, J=8.1 Hz), 4.69 (1H, sept, J=6.0Hz), 4.60 (2H, dd, J=5.1 Hz, 0.9 Hz), 4.15 (2H, dd, J=14.1 Hz, 6.9 Hz),1.48 (3H, t, J=6.9 Hz), 1.40 (6H, d, J=6.3 Hz).

Synthesis of Compound (11q)

The procedure in “Synthesis of Compound (11i)” above was repeated usingcompound (iii) and 2-ethoxy-3,4-dihydroxybenzoic acid, thereby obtainingN-[2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxy-3,4-dihydroxybenzamide(N-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methyl)-2-ethoxy-3,4-dihydroxybenzamide:compound (11q)).

¹H-NMR (d6-DMSO) δ: 9.83 (1H, brs), 8.65 (1H, brs), 8.54 (1H, t, J=5.4Hz), 8.10 (1H, s), 7.63 (1H, d, J=1.8 Hz), 7.56 (1H, dd, J=8.4 Hz, 1.8Hz), 7.33 (1H, d, J=8.4 Hz), 7.21 (1H, d, J=8.7 Hz), 7.15 (1H, t, J=74Hz), 6.62 (1H, d, J=8.4 Hz), 4.73 (1H, sept, J=6.0 Hz), 4.45 (2H, d,J=5.4 Hz), 4.03 (2H, dd, J=14.1 Hz, 7.2 Hz), 1.32 (6H, d, J=6.0 Hz),1.25 (3H, t, J=7.2 Hz).

Synthesis of Compound (11r)

A typical synthesis procedure was performed using 0.1 g of compound(11a) and chlorosulfuric acid, thereby obtainingN-[(2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-yl)methylcarbamoyl]-2-phenylammonium sulfate (ammonium2-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methylcarbamoyl)phenylsulfate (compound (11r)) as a white powder. The melting point was 162.0°C.

Synthesis of Compound (11s)

A typical synthesis procedure was performed using 0.1 g of compound(11a), 1-bromo-2,3,4-tri-O-acetyl-α-D-glucuronic acid methyl, and silveroxide, thereby obtaining(2S,3S,4S,5R,6S)-6-(2-((2-(3-isopropoxy-4-difluoromethoxyphenyl)oxazol-4-yl)methylcarbamoyl)phenyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylicacid((2S,3S,4S,5R,6S)-6-(2-((2-(4-(difluoromethoxy)-3-isopropoxyphenyl)oxazol-4-yl)methylcarbamoyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid: compound(11s)) as a white powder. The melting point was 163.6° C.

Production Example 7: Production of Formulations Study of Solvent

To select a solvent for dissolving compound (11) in preparing anointment containing compound (11), the solubility of compound (11) invarious solvents was studied. Even a solvent having a high solubility ofcompound (11) exhibits reduced solubility of compound (11) if it hascompatibility with a base material (ointment base), such as petrolatumor paraffin, and is mixed with the base material. Such a case may resultin precipitation of compound (11). Thus, a solvent that has a highsolubility of compound (11) but that has no or low miscibility(compatibility) with petrolatum or paraffin is relatively preferable foruse. Table 4 shows the results of the study.

TABLE 4 Miscibility of Compound (11) Solubility Solvent Solvent Solutionwith Petrolatum (W/W %) Triacetine Immiscible 32.5 Propylene carbonateImmiscible 56.9 Diethyl sebacate Miscible 42.6 Diisopropyl adipateMiscible 40.3 Isostearic acid Miscible 19.8 Olive oil Miscible 6.1Isopropyl myristate Miscible 6.0 Hexyldodecanol Miscible 5.4 Isostearylalcohol Miscible 5.1 Decyl oleate Miscible 2.6 Liquid Paraffin Miscible0.1

Table 4 indicates that triacetin and propylene carbonate have lowmiscibility with petrolatum, and also indicates that triacetin andpropylene carbonate have a relatively high solubility of compound (11).

Formulation of Ointment

Ointments (Examples 1 to 10 and Comparative Examples 1 to 8) wereprepared as described below. As noted above, solvents that dissolvecompound (11) were found. Thus, the present invention encompasses all ofthe ointments prepared by dissolving compound (11) in a solvent.However, of these, the following describes particularly preferableexamples as Examples, and others as Comparative Examples forconvenience. The particle size of droplets is measured by placing asuitable amount of a prepared ointment on a glass slide and observingthe droplet size with a polarizing microscope.

Example 1

73.0 g of white petrolatum, 10.0 g of liquid paraffin, 3.0 g ofparaffin, and 1.0 g of beeswax (non-chemically bleached beeswax) wereheated and dissolved at 70° C. in an agi-homomixer. Thereafter, asolution of 3.0 g of compound (11) in 10.0 g of propylene carbonate wasfurther added thereto, and the mixture was stirred with a homomixer at5000 rpm and with a paddle at 30 rpm. The homomixer was then turned offat 45° C., and the paddle and cooling were turned off at 40° C. to givea droplet size of 20 μm or less. Thereafter, the resulting product wasinserted into aluminum tubes, 5 g in each tube, with a YS-7 fillingmachine, and the tubes were sealed, thereby obtaining ointments.

Example 2

The procedure of Example 1 was repeated except that 72.0 g of whitepetrolatum and 2.0 g of beeswax were used, thereby obtaining ointments.

Example 3

The procedure of Example 1 was repeated except that 70.5 g of whitepetrolatum and 3.5 g of beeswax were used, thereby obtaining ointments.

Example 4

The procedure of Example 1 was repeated except that 81.0 g of whitepetrolatum, 1.0 g of compound (11), and 4.0 g of propylene carbonatewere used, thereby obtaining ointments.

Example 5

The procedure of Example 4 was repeated except that 80.0 g of whitepetrolatum and 2.0 g of beeswax were used, thereby obtaining ointments.

Example 6

The procedure of Example 4 was repeated except that 78.5 g of whitepetrolatum and 3.5 g of beeswax were used, thereby obtaining ointments.

Example 7

The procedure of Example 6 was repeated except that 79.2 g of whitepetrolatum and 0.3 g of compound (11) were used, thereby obtainingointments.

Example 8

The procedure of Example 6 was repeated except that 79.4 g of whitepetrolatum and 0.1 g of compound (11) were used, thereby obtainingointments.

Example 9

70.5 g of white petrolatum, 10.0 g of liquid paraffin, 3.0 g ofparaffin, and 3.5 g of beeswax (chemically bleached beeswax) were heatedand dissolved at 70° C. in an agi-homomixer. Thereafter, a solution of3.0 g of compound (11) in 10.0 g of propylene carbonate was furtheradded thereto, and the mixture was stirred with a homomixer at 5000 rpmand with a paddle at 30 rpm. The homomixer was then turned off at 45°C., and the paddle and cooling were turned off at 40° C. to give adroplet size of 20 μm or less. Thereafter, resulting product wasinserted into aluminum tubes, 5 g in each tube, with a YS-7 fillingmachine, and the tubes were sealed, thereby obtaining ointments.

Example 10

The procedure of Example 3 was repeated except that 73.5 g of whitepetrolatum and 7.0 g of propylene carbonate were used, thereby obtainingointments.

Comparative Example 1

The procedure of Example 4 was repeated except that 82.0 g of whitepetrolatum was used, and that beeswax was not added, thereby obtainingointments.

Comparative Example 2

58.5 g of white petrolatum, 6.0 g of paraffin, 6.0 g of beeswax, and 5.0g of diethyl sebacate were heated and dissolved at 70° C. by handstirring in a 200-mL beaker. After cooling to 50° C., 17 g of liquidparaffin was added thereto, and the mixture was heated to 50° C. 13 g ofa paste containing 10 g of liquid paraffin and 3 g of micronizedcompound (11) was added thereto and mixed well by hand stirring, withthe temperature maintained at 50° C. The mixture was cooled to roomtemperature with ice water. Thereafter, the mixture was inserted intoaluminum tubes, 5 g in each tube, with a YS-7 filling machine, therebyobtaining ointments.

Micronized compound (11) was obtained by adding compound (11) to liquidparaffin and pulverizing the mixture with a DYNO-MILL (bead mill).Thus-obtained paste was used in the operation above.

Comparative Example 3

The procedure of Example 3 was repeated except that 75.5 g of whitepetrolatum and 5.0 g of propylene carbonate were used, thereby obtainingointments.

Comparative Example 4

The procedure of Example 6 was repeated except that 80.5 g of whitepetrolatum and 2.0 g of propylene carbonate were used, thereby obtainingointments.

Comparative Example 5

The procedure of Example 6 was repeated except that 79.5 g of whitepetrolatum was used, and that compound (11) was not added, therebyobtaining ointments.

Comparative Example 6

The procedure of Example 3 was repeated except that the mixture wasstirred with a homomixer at 1500 rpm and with a paddle at 15 rpm,thereby preparing an ointment having a droplet size of about 50 μm.

Comparative Example 7

The procedure of Example 6 was repeated except that the mixture wasstirred with a homomixer at 1500 rpm and with a paddle at 15 rpm,thereby preparing an ointment having a droplet size of about 50 μm.

Comparative Example 8

The procedure of Example 7 was repeated except that the mixture wasstirred with a homomixer at 1500 rpm and with a paddle at 15 rpm,thereby preparing an ointment having a droplet size of about 50 μm.

Table 5 shows the compositions of formulations described above.

TABLE 5 Component and Amount of Component (w/w %) White Liquid PropyleneDiethyl State of Droplet Size Formulation Compound(11) PetrolatumParaffin Paraffin Beeswax Carbonate Sebacate Formulation (Particle Size)Example 1 3 73 10 3 1 10 — Homogeneous droplet- 20 μm or less dispersionointment Example 2 3 72 10 3 2 10 — Homogeneous droplet- 20 μm or lessdispersion ointment Example 3 3 70.5 10 3 3.5 10 — Homogeneous droplet-20 μm or less dispersion ointment Example 4 1 81 10 3 1 4 — Homogeneousdroplet- 20 μm or loss dispersion ointment Example 5 1 80 10 3 2 4 —Homogeneous droplet- 20 μm or less dispersion ointment Example 6 1 78.510 3 3.5 4 — Homogeneous droplet- 20 μm or less dispersion ointmentExample 7 0.3 79.2 10 3 3.5 4 — Homogeneous droplet- 20 μm or lessdispersion ointment Example 8 0.1 79.4 10 3 3.5 4 — Homogeneous droplet-20 μm or less dispersion ointment Example 9 3 70.5 10 3 3.5 10 —Homogeneous droplet- 20 μm or less dispersion ointment Example 10 3 73.510 3 3.5 7 — Homogeneous droplet- 20 μm or less dispersion ointmentComparative 1 82 10 3 — 4 — Homogeneous droplet- 20 μm or less Example 1dispersion ointment Comparative 3 58.5 27 6 5 — 5 Homogenous ointment 20μm or less Example 2 in which crystals are (crystalline dispersedparticle size) Comparative 3 75.5 10 3 3.5 5 — Homogeneous ointment —Example 3 Comparative 1 80.5 10 3 3.5 2 — Homogeneous ointment — Example4 Comparative — 79.5 10 3 3.5 4 — Homogeneous droplet- — Example 5dispersion ointment Comparative 3 70.5 10 3 3.5 10 — Inhomogeneous Morethan Example 6 droplet-dispersion 50 μm ointment Comparative 1 78.5 10 33.5 4 — Inhomogeneous More than Example 7 droplet-dispersion 50 μmointment Comparative 0.3 79.2 10 3 3.5 4 — Inhomogeneous More thanExample 8 droplet-dispersion 50 μm ointmentStudy into Formulation Stability 1

The ointments prepared in Comparative Example 1 and Examples 4, 5, and 6were allowed to stand at 40° C. for 2 months. Thereafter, the dispersionstate of the propylene carbonate solution in each formulation wasexamined. Table 6 shows the results. Table 6 reveals that beeswaxmaintains the homogeneous dispersion state, and thus improves stability.

TABLE 6 Formulation Amount of Beeswax Dispersion State Comparative 0 Theparticle size Example 1 was increased. Example 4 1.0 Excellent Example 52.0 Excellent Example 6 3.5 ExcellentStudy into Formulation Stability 2

The ointments prepared in Comparative Example 1 and Examples 1 to 6 aredifferent in the amount of beeswax added. These formulations weresubjected to a stability test at 50° C. for 2 weeks, 4 weeks, or 6weeks. To examine the degree of decomposition of compound (11), theamount of generated 3-(2-propoxy 3-difluoromethoxy)benzamide, which isone of the decomposed matters, was measured by high-performance liquidchromatography. Table 7 shows the results. The values in Table 7indicate the concentration (wt %) of compound (11), beeswax, and thedecomposed matter in each formulation. While Comparative Example 1, towhich beeswax was not added, generated about 1% of the decomposedmatter, the formulations made by adding beeswax exhibited reducedgeneration of the decomposed matter.

TABLE 7 Concentration Amount of of Compound Beeswax After 2 After 4After 6 Formulation (11) (%) Added (%) weeks weeks weeks Comparative 1.00 0.90 0.99 0.97 Example 1 Example 4 1.0 1.0 0.00 <0.05 <0.05 Example 51.0 2.0 0.00 0.00 0.00 Example 6 1.0 3.5 0.00 <0.05 <0.05 Example 1 3.01.0 <0.05 0.23 0.18 Example 2 3.0 2.0 0.00 0.00 <0.05 Example 3 3.0 3.50.00 0.00 <0.05Study into Formulation Stability 3

The formulation of the formulation of Example 3 was prepared usingbeeswax that was not bleached (unbleached beeswax), beeswax bleached bynon-chemical purification (non-chemically bleached beeswax), or beeswaxthat was chemically bleached (chemically bleached beeswax) as beeswax,and the formulation was inserted into aluminum tubes, and sealed,followed by storage at 50° C. for 2 weeks, 4 weeks, or 8 weeks. In thesame manner as above, with the generated decomposed matter of compound(11) (3-(2-propoxy 3-difluoromethoxy)benzamide) as an index, thestability of compound (11) was examined. Table 8 shows the results.While the use of chemically bleached beeswax generated a high amount ofthe decomposed matter, the use of non-chemically bleached beeswax andunbleached beeswax exhibited reduced generation of the decomposedmatter.

TABLE 8 After 2 After 4 After 8 Type of Beeswax Weeks weeks weeksChemically Bleached Beeswax Produced by 0.19 0.20 0.16 Company ANon-Chemically Bleached Beeswax 0.00 0.00 0.00 Produced by Company AUnbleached Beeswax Produced by Company 0.00 0.00 0.00 A Non-ChemicallyBleached Beeswax 0.00 0.00 0.00 Produced by Company C ChemicallyBleached Beeswax Produced by 0.18 0.16 0.25 Company DStudy into Formulation Stability 4

Ointments containing compound (11) and different amounts of beeswax wereprepared. A predetermined amount of each ointment was placed on a glassslide, and the droplet size of each ointment was confirmed with apolarizing microscope to search for the amount of beeswax necessary toobtain an ointment in which droplets are excellently dispersed. Theointments (Examples 11 to 19 and Comparative Examples 9 to 11) wereprepared as described below. The present invention encompasses all ofthe ointments containing beeswax. However, of these, the followingdescribes particularly preferable examples as Examples, and others asComparative Examples for convenience.

Example 11

141.0 g of white petrolatum, 20.0 g of liquid paraffin, 6.0 g ofparaffin, and 7.0 g of beeswax (non-chemically bleached beeswax) wereheated and dissolved at 70° C. in an agi-homomixer. Thereafter, asolution of 6.0 g of compound (11) in 20.0 g of propylene carbonate wasfurther added thereto, and the mixture was stirred with a homomixer at5000 rpm and with a paddle at 30 rpm, followed by cooling. The homomixerwas turned off at 45° C. and the paddle and cooling were turned off at40° C. The resulting product was inserted into aluminum tubes, 5 g ineach tube, with a YS-7 filling machine, and the tubes were sealed,thereby obtaining ointments.

Example 12

The procedure of Example 11 was repeated except that 146.0 g of whitepetrolatum and 2.0 g of beeswax were used, thereby obtaining ointments.

Example 13

The procedure of Example 11 was repeated except that 146.4 g of whitepetrolatum and 1.6 g of beeswax were used, thereby obtaining ointments.

Example 14

The procedure of Example 11 was repeated except that 146.8 g of whitepetrolatum and 1.2 g of beeswax were used, thereby obtaining ointments.

Comparative Example 9

The procedure of Example 11 was repeated except that 147.2 g of whitepetrolatum and 0.8 g of beeswax were used, thereby obtaining ointments.

Comparative Example 10

The procedure of Example 11 was repeated except that 147.6 g of whitepetrolatum and 0.4 g of beeswax were used, thereby obtaining ointments.

Example 15

157.0 g of white petrolatum, 20.0 g of liquid paraffin, 6.0 g ofparaffin, and 7.0 g of beeswax (non-chemically bleached beeswax) wereheated and dissolved at 70° C. in an agi-homomixer. Thereafter, asolution of 2.0 g of compound (11) in 8.0 g of propylene carbonate wasfurther added thereto, and the mixture was stirred with a homomixer at5000 rpm and with a paddle at 30 rpm, followed by cooling. The homomixerwas turned off at 45° C., and the paddle and cooling were turned off at40° C. The resulting product was inserted into aluminum tubes, 5 g ineach tube, with a YS-7 filling machine, and the tubes were sealed,thereby obtaining ointments.

Example 16

The procedure of Example 15 was repeated except that 162.0 g of whitepetrolatum and 2.0 g of beeswax were used, thereby obtaining ointments.

Example 17

The procedure of Example 15 was repeated except that 162.4 g of whitepetrolatum and 1.6 g of beeswax were used, thereby obtaining ointments.

Example 18

The procedure of Example 15 was repeated except that 162.8 g of whitepetrolatum and 1.2 g of beeswax were used, thereby obtaining ointments.

Example 19

The procedure of Example 15 was repeated except that 163.2 g of whitepetrolatum and 0.8 g of beeswax were used, thereby obtaining ointments.

Comparative Example 11

The procedure of Example 15 was repeated except that 163.6 g of whitepetrolatum and 0.4 g of beeswax were used, thereby obtaining ointments.

Table 9 shows the formulations and the state of the dispersion ofdroplets of the ointments. The unit is wt %. Table 9 reveals that whenan ointment containing 3 parts by weight of component (11) contains 0.6parts by weight or more of beeswax, the ointment exhibits particularlyexcellent dispersion of the droplets, and that when an ointmentcontaining 1 part by weight of compound (11) contains 0.4 parts byweight or more of beeswax, the ointment exhibits particularly excellentdispersion of the droplets.

TABLE 9 Component and Amount of Component (w/w %) White Liquid PropyleneState of Formulation Compound(11) Petrolatum Paraffin Paraffin BeeswaxCarbonate Formulation Example 11 3.0 70.5 10.0 3.0 3.5 10.0Droplet-dispersion ointment having a particle size of 20 μm or lessExample 12 3.0 73.0 10.0 3.0 1.0 10.0 Droplet-dispersion ointment havinga particle size of 20 μm or less Example 13 3.0 73.2 10.0 3.0 0.8 10.0Droplet-dispersion ointment having a particle size of 20 μm or lessExample 14 3.0 73.4 10.0 3.0 0.6 10.0 Droplet-dispersion ointment havinga particle size of 20 μm or less Comparative 3.0 73.6 10.0 3.0 0.4 10.0Droplet-dispersion Example 9 ointment having a particle size of morethan 20 μm Comparative 3.0 73.8 10.0 3.0 0.2 10.0 Droplet-dispersionExample 10 ointment having a particle size of more than 50 μm Example 151.0 78.5 10.0 3.0 3.5 4.0 Droplet-dispersion ointment having a particlesize of 20 μm or less Example 16 1.0 81.0 10.0 3.0 1.0 4.0Droplet-dispersion ointment having a particle size of 20 μm or lessExample 17 1.0 81.2 10.0 3.0 0.8 4.0 Droplet-dispersion ointment havinga particle size of 20 μm or less Example 18 1.0 81.4 10.0 3.0 0.6 4.0Droplet-dispersion ointment having a particle size of 20 μm or lessExample 19 1.0 81.6 10.0 3.0 0.4 4.0 Droplet-dispersion ointment havinga particle size of 20 μm or less Comparative 1.0 81.8 10.0 3.0 0.2 4.0Droplet-dispersion Example 11 ointment having a particle size of morethan 20 μm

1. An ointment comprising an oxazole compound represented by thefollowing formula (11):


2. The ointment according to claim 1, comprising the oxazole compounddissolved in a base component.
 3. The ointment according to claim 2,wherein the base component comprises a solvent for dissolving theoxazole compound in the solvent, and an ointment base for dispersing ordissolving the solvent in the ointment base.
 4. The ointment accordingto claim 3, wherein the ointment base comprises a hydrocarbon.
 5. Theointment according to claim 3, wherein the solvent comprises a polarcompound that is a liquid at room temperature.
 6. The ointment accordingto claim 3, wherein the ointment base is an ointment base for dispersingthe solvent in the ointment base, and the solvent in the form ofdroplets, in which the oxazole compound is dissolved, is dispersed inthe ointment base.
 7. The ointment according to claim 3, wherein theointment base comprises at least beeswax.
 8. The ointment according toclaim 7, wherein the beeswax is not chemically bleached.
 9. A method fortreatment and/or prevention of eczema and dermatitis, comprisingapplying the ointment according to claim 1 to a subject in need thereof.10. A method of producing an oxazole compound represented by thefollowing formula (11):

the method comprising the following reaction scheme: